Compounds useful as reversible inhibitors of cysteine proteases

ABSTRACT

Disclosed are novel cathepsin S, K, F, L and B reversible inhibitory compounds of the formula (Ia) and (Ib) where R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , Het and X are defined herein. The compounds are useful for treating autoimmune and other diseases. Also disclosed are processes for making such novel compounds.

RELATED APPLICATION DATA

[0001] This application is a divisional of U.S. application Ser. No.10/261,994 filed Oct. 1, 2002 which is divisional of U.S. applicationSer. No. 09/808,439 filed Mar. 14, 2001 which is a continuation-in-partof U.S. application Ser. No. 09/655,351 filed Sep. 8, 2000.

TECHNICAL FIELD OF THE INVENTION

[0002] This invention relates to amidino and guanidino peptidylcompounds active as cysteine protease inhibitors. The compounds arereversible inhibitors of the cysteine protease cathepsin S, K, F, L andB are therefore useful in the treatment of autoimmune and otherdiseases. The invention also relates to processes for preparing suchcompounds and pharmaceutical compositions comprising them.

BACKGROUND OF THE INVENTION

[0003] Cathepsin S and cathepsin K are members of the papain family,within the papain superfamily of cysteine proteases. The papain familyis the largest group of cysteine proteases and includes proteases suchas cathepsins B, H, K, L, O and S. (A. J. Barrett et al., 1996,Perspectives in Drug Discovery and Design, 6, 1). The cysteine proteaseshave important roles in human biology and diseases includingatherosclerosis, emphysema, osteoporosis, chronic inflammation andimmune disorders (H. A. Chapman et al., 1997, Ann. Rev. Physiol., 59,63). Cathepsin S plays a key role in regulating antigen presentation andimmunity (H. A. Chapman, 1998, Current Opinion in Immunology, 10, 93; R.J. Riese et al., 1998, J. Clin. Invest., 101, 2351; R. J. Riese et al.,1996, Immunity, 4, 357). Cathepsin S deficient mice have impairedinvariant chain degradation resulting in decreased antigen presentationand germinal center formation, and diminished susceptibility tocollagen-induced arthritis indicating the therapeutic potential for acathepsin S inhibitor (G. Shi et al., 1999, Immunity, 10, 197; T. Y.Nakagawa et al, 1999, Immunity, 10, 207)

[0004] The specificity of the immune response relies on processing offoreign protein and presentation of antigenic peptide at the cellsurface. Antigenic peptide is presented bound to MHC Class II, aheterodimeric glycoprotein expressed in certain antigen presenting cellsof hematopoietic lineage, such as B cells, macrophages and dendriticcells. Presentation of antigen to effector cells, such as T-cells, is afundamental step in recognition of non-self and thus initiation of theimmune response.

[0005] Recently MHC Class II heterodimers were shown to associateintracellularly with a third molecule designated invariant chain.Invariant chain facilitates Class II transport to the endosomalcompartment and stabilizes the Class II protein prior to loading withantigen. Invariant chain interacts directly with Class II dimers in theantigen-binding groove and therefore must be proteolyzed and removed orantigen cannot be loaded or presented. Current research suggests thatinvariant chain is selectively proteolyzed by cathepsin S, which iscompartmentalized with MHC Class II complexes within the cell. CathepsinS degrades invariant chain to a small peptide, termed CLIP, whichoccupies the antigen-binding groove. CLIP is released from MHC Class IIby the interaction of MHC Class II with HLA-DM, a MHC-like molecule thusfreeing MHC Class II to associate with antigenic peptides. MHC ClassII-antigen complexes are then transported to the cell surface forpresentation to T-cells, and initiation of the immune response.

[0006] Cathepsin S, through proteolytic degradation of invariant chainto CLIP, provides a fundamental step in generation of an immuneresponse. It follows that inhibition of antigen presentation viaprevention of invariant chain degradation by cathepsin S could provide amechanism for immuno-regulation. Control of antigen-specific immuneresponses has long been desirable as a useful and safe therapy forautoimmune diseases. Such diseases include Crohn's disease andarthritis, as well as other T-cell-mediated immune responses (C. Janewayand P. Travers, 1996, Immunobiology, The Immune System in Health andDisease, Chapter 12). Furthermore, cathepsin S, which has broad pHspecificity, has been implicated in a variety of other diseasesinvolving extracellular proteolysis, such as Alzheimer's disease (U.Muller-Ladner et al., 1996, Perspectives in Drug Discovery and Design,6, 87), atherosclerosis (G.K. Sukhova et al., 1998, J. Clin. Invest.,102, 576) and endometriosis (WO 9963115, 1999).

[0007] A cathepsin S inhibitor has been found to block the rise in IgEtiters and eosinophil infiltration in the lung in a mouse model ofpulmonary hypersensitivity, suggesting that cathepsin S may be involvedin asthma (R. J. Riese et al., J. Clin. Investigation, 1998, 101, 2351).

[0008] Another cysteine protease, cathepsin F has been found inmacrophages and is also involved in antigen processing. It has beenpostulated that cathepsin F in stimulated lung macrophages and possiblyother antigen presenting cells could play a role in airway inflammation(G.-P. Shi et al., J. Exp. Med., 2000, 191, 1177).

[0009] Cathepsin K, another cysteine protease has been found to behighly expressed in osteoclasts and to degrade bone collagen and otherbone matrix proteins. Inhibitors of cathepsin K have been shown toinhibit bone resorption in mice. Therefore, cathepsin K may play a rolein osteoclastic bone resorption and cathepsin K inhibitors may be usefulin the treatment of diseases involving bone resorption such asosteoporosis (F. Lazner et al., Human Molecular Genetics, 1999, 8,1839).

[0010] Cysteine proteases are characterized by having a cysteine residueat the active site which serves as a nucleophile. The active site alsocontains a histidine residue. The imidazole ring on the histidine servesas a base to generate a thiolate anion on the active site cysteine,increasing its nucleophilicity. When a substrate is recognized by theprotease, the amide bond to be cleaved is directed to the active site,where the thiolate attacks the carbonyl carbon forming an acyl-enzymeintermediate and cleaving the amide bond, liberating an amine.Subsequently, water cleaves the acyl-enzyme species regenerating theenzyme and liberating the other cleavage product of the substrate, acarboxylic acid.

[0011] Inhibitors of cysteine proteases contain a functionality that canreact reversibly or irreversibly with the active site cysteine. Examplesof reactive functionalities that have been described (D. Rasnick, 1996,Perspectives in Drug Discovery and Design, 6, 47) on cysteine proteaseinhibitors include peptidyl diazomethanes, epoxides, monofluoroalkanesand acyloxymethanes, which irreversibly alkylate the cysteine thiol.Other irreversible inhibitors include Michael acceptors such as peptidylvinyl esters and other carboxylic acid derivatives (S. Liu et al., J.Med Chem., 1992, 35, 1067) and vinyl sulfones (J. T. Palmer et al.,1995, J. Med Chem., 38, 3193).

[0012] Reactive functionalities that form reversible complexes with theactive site cysteine include peptidyl aldehydes (R. P. Hanzlik et al.,1991, Biochim. Biophys. Acta., 1073, 33), which are non-selective,inhibiting both cysteine and serine proteases as well as othernucleophiles. Peptidyl nitriles (R. P. Hanzlik et al., 1990, Biochim.Biophys. Acta., 1035, 62) are less reactive than aldehydes and thereforemore selective for the more nucleophilic cysteine proteases. Variousreactive ketones have also been reported to be reversible inhibitors ofcysteine proteases (D. Rasnick, 1996, ibid). In addition to reactingwith the nucleophilic cysteine of the active site, reactive ketones mayreact with water, forming a hemiketal which may act as a transitionstate inhibitor.

[0013] Examples of cathepsin S inhibitors have been reported. J. L.Klaus et al. (WO 9640737) described reversible inhibitors of cysteineproteases including cathepsin S, containing an ethylene diamine. In U.S.Pat. No. 5,776,718 to Palmer et al. there is disclosed in it's broadestgeneric aspect a protease inhibitor comprising a targeting group linkedthrough a two carbon atom chain to an electron withdrawing group (EWG).The compounds of the present application are structurally distinct andthus excluded from the U.S. Pat. No. 5,776,718 patent with particularembodiments possessing unexpectedly greater activity than the closestcompounds of the prior art. Other examples of cathepsin S inhibitorshave been reported by E. T. Altmann et al, (WO 9924460, 1999) whichdescribes dipeptide nitriles asserted to have activity as inhibitors ofCathepsins B, K, L and S. The WO publication does not disclose anycompounds possessing a guanidino or amidino structure at the P3position.

[0014] Additional peptidyl nitrites have been reported as proteaseinhibitors. For example, both nitrites and ketoheterocycles aredescribed by B. A. Rowe et al. (U.S. Pat. No. 5,714,471) as proteaseinhibitors useful in the treatment of neurodegenerative diseases.Peptidyl nitrites are reported by B. Malcolm et al. (WO 9222570) asinhibitors of picornavirus protease. B. J. Gour-Salin (Can. J. Chem.,1991, 69, 1288) and T. C. Liang (Arch. Biochim. Biophys., 1987, 252,626) described peptidyl nitrites as inhibitors of papain

[0015] A reversible inhibitor presents a more attractive therapy thanirreversible inhibitors. Even compounds with high specificity for aparticular protease can bind non-target enzymes. An irreversiblecompound could therefore permanently inactivate a non-target enzyme,increasing the likelihood of toxicity. Furthermore, any toxic effectsresulting from inactivation of the target enzyme would be mitigated byreversible inhibitors, and could be easily remedied by modified or lowerdosing. Finally, covalent modification of an enzyme by an irreversibleinhibitor could potentially generate an antibody response by acting as ahapten.

[0016] In light of the above, there is a clear need for compounds whichreversibly and selectively inhibit cysteine proteases such as cathepsinS and cathepsin K for indications in which these proteases exacerbatedisease.

BRIEF DESCRIPTION OF THE INVENTION

[0017] It is therefore an object of this invention to provide novelcompounds according to the formulas (Ia) and (Ib) as desrcribed hereinwhich reversibly inhibit the cysteine proteases cathepsin S, K, F, L andB. It is a further object of the invention to provide methods fortreating diseases and pathological conditions exacerbated by thesecysteine proteases such as, but not limited, to rheumatoid arthritis,multiple sclerosis, asthma and osteoporosis. It is yet a further objectof the invention to provide novel processes for preparation of theabove-mentioned novel compounds.

DETAILED DESCRIPTION OF THE INVENTION

[0018] A proposed mechanism of action of the cysteine proteaseinhibitors of this invention is that the inhibitors contain afunctionality that can react (reversibly or irreversibly) with theactive site cysteine. The reactive functionality is attached to apeptide or peptide mimic that can be recognized and accommodated by theregion of the protease surrounding the active site. The nature of boththe reactive functionality and the remaining portion of the inhibitordetermine the degree of selectivity and potency toward a particularprotease.

[0019] Given the similarity of the active sites in cysteine proteases,it may be anticipated that a given class of inhibitors might haveactivity against more that one cysteine protease. It may also beexpected that due to structural differences between individual cysteineproteases, different compounds of the invention may have differentinhibitory potencies against different cysteine proteases. Thus some ofthe compounds of the invention may also be expected to be most effectivein treating diseases mediated by cysteine proteases that they inhibitmost potently. The activity of particular compounds disclosed hereinagainst cysteine proteases such as cathepsin S, K, F, L and B may bedetermined by the screens described in the section entitled “Assessmentof Biological Properties.”

[0020] Accordingly, in a first generic aspect of the invention, thereare provided compounds of formula (Ia) and (Ib):

[0021] wherein:

[0022] Het is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl, oxepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,azocanyl, oxocanyl, 1,3-diazocanyl, 1,4-diazocanyl, 1,5-diazocanyl,1,3-dioxocanyl, 1,4-dioxocanyl, 1,5-dioxocanyl, 1,3-oxazocanyl,1,4-oxazocanyl, 1,5-oxazocanyl, 1,3-diazepanyl, 1,4-diazepanyl,1,3-dioxepanyl, 1,4-dioxepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl,1,2-thiazocanyl-1,1-dioxide, 1,2,8-thiadiazocanyl-1,1-dioxide,1,2-thiazepanyl-1,1-dioxide, 1,2,7-thiadiazepanyl-1,1-dioxide,tetrahydrothiophenyl, hexahydropyrimidinyl, hexahydropyridazinyl,piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl,dihydro-oxazolyl, dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl,oxazolidinyl, 1,2-thiazinanyl-1,1-dioxide,1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide,imidazolidinyl-2,4-dione, imidazolidinyl, morpholinyl, dioxanyl,tetrahydropyridinyl, thiomorpholinyl, thiazolidinyl, dihydropyranyl,dithianyl, decahydro-quinolinyl, decahydro-isoquinolinyl,1,2,3,4-tetrahydro-quinolinyl, indolinyl, octahydro-quinolizinyl,dihydro-indolizinyl, octahydro-indolizinyl, octahydro-indolyl,decahydroquinazolinyl, decahydroquinoxalinyl,1,2,3,4-tetrahydroquinazolinyl or 1,2,3,4-tetrahydroquinoxalinyl;

[0023] A C6-C10 bridged bicyclo wherein one or more carbon atoms areoptionally replaced by a heteroatom chosen from N, O and S;

[0024] each being optionally substituted with one or more R₅;

[0025] R₁ is a bond, hydrogen, C1-10 alkyl, C1-10 alkoxy, aryloxy, C3-8cycloalkyl, C3-8 cycloalkyloxy, aryl, benzyl, tetrahydronaphthyl,indenyl, indanyl, C1-10alkylsulfonylC1-10alkyl,C3-8cycloalkylsulfonylC1-10alkyl, arylsulfonylC1-10alkyl, heterocyclylselected from azepanyl, azocanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl,tetrahydropyranyl, tetrahydrothiopyranyl, thiopyranyl, furanyl,tetrahydrofuranyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl,pyrazolyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, benzisoxazolyl, quinolinyl, tetrahydroquinolinyl,isoquinolinyl, tetrahydroisoquinolinyl, quinazolinyl,tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl, heterocyclyloxywherein the heterocyclyl moiety is selected from those herein describedin this paragraph, hydroxy or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

[0026] R_(a) is a bond, C1-10 alkyl, C3-8 cycloalkyl, aryl,tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl, benzisoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, C1-10alkanoyl,C1-10alkanoyloxy, aryloxy, benzyloxy, C1-10 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

[0027] or R_(a) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0028] or R_(a) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino,C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0029] or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0030] with the proviso that R₁ and R_(a) simultaneously cannot be abond;

[0031] R_(b) is a C1-6 saturated or unsaturated branched or unbranchedcarbon chain optionally partially or fully halogenated wherein one ormore carbon atoms are optionally replaced by O, N, S(O), S(O)₂ or S andwherein said chain is optionally independently substituted with 1-2 oxogroups, —NH₂, or one or more C1-4 alkyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl;

[0032] or R_(b) is C3-6 cycloalkyl, aryl, aryloxy, benzyloxy, halogen,hydroxy, oxo, carboxy, cyano, nitro, mono-C1-5alkylamino,di-C1-5alkylamino, carboxamide, amidino or guanidino;

[0033] R₂ is hydrogen or C1-3 alkyl;

[0034] R₃ is a bond, hydrogen, C1-10 alkyl, C2-10alkylene, C3-8cycloalkyl, arylC1-5alkyl or aryl wherein R₃ is optionally substitutedby one or more R_(c);

[0035] R_(c) is C1-10 alkyl, C3-8 cycloalkyl, aryl, indanyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, decahydronaphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl,tetrahydrothiopyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, dihydrobenzofuranyl, octohydrobenzofuranyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,tetrahydroquinolinyl, quinolinyl, tetrahydroisoquinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-10 alkoxy, aryloxy, C1-10alkanoyl, aroyl, C1-10 alkoxycarbonyl, aryloxycarbonyl, C1-10alkanoyloxy, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

[0036] or R_(c) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0037] or R_(c) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino,C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0038] or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoor guanidino, R_(c) may be further optionally substituted by one or moreR_(d);

[0039] R_(d) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-5alkyl, C1-5alkoxy, aryloxy, arylC1-5alkoxy, aroyl, amino, halogen, hydroxy, oxo,carboxy, cyano, nitro, amidino or guanidino;

[0040] R₂ and R₃ together with the carbon they are attached optionallyform a nonaromatic 5-7 membered cycloalkyl or heterocyclic ring;

[0041] each R₄ is independently hydrogen, hydroxy or C1-3 alkyl;

[0042] R₅ is a bond, hydrogen, carbonyl, C1-10 alkyl,C1-10alkoxyC1-10alkyl, C1-10alkylaminoC1-10alkyl,C1-10alkylthioC1-10alkyl wherein the sulfur atom may be oxidized to asulfoxide or sulfone, C1-10 alkoxy, aryloxy, C3-8 cycloalkyl, aryl,benzyl, tetrahydronaphthyl, indenyl, indanyl,C3-7cycloalkylsulfonylC1-5alkyl, arylsulfonylC1-5alkyl, heterocyclylselected from pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, tetrahydropyranyl, thiopyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, pyrrolyl,oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridizinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl and quinoxalinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-10alkanoyl, aroyl,C1-10alkanoyloxy, benzyloxy, C1-10alkoxycarbonyl,arylC1-5alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-10alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

[0043] or R₅ is C1-10 alkanoylamino, aroylamino, C1-10 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, arylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0044] or R₅ is C1-10 alkoxycarbonylamino, aryloxycarbonylamino, C1-10alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0045] or R₅ is halogen, hydroxy, oxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R₅ may be further optionallysubstituted by one or more R_(e);

[0046] R_(e) is C1-10 alkyl, C1-10alkoxyC1-10alkyl,C1-10alkylaminoC1-10alkyl, C1-10alkylthioC1-10alkyl wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, C1-10 alkoxy, C3-8cycloalkyl, aryl, tetrahydronaphthyl, indenyl, indanyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,thiopyranyl, tetrahydrothiopyranyl, pyranyl, tetrahydropyranyl,tetrahydrofuranyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, benzisoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, C1-10alkanoyl, aroyl, C1-10alkanoyloxy, aryloxy,benzyloxy, C1-10 alkoxycarbonyl, arylC1-3alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-10 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

[0047] or R_(e) is C1-10 alkanoylamino, aroylamino, C1-10 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-10 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0048] or R_(e) is C1-10 alkoxycarbonylamino, aryloxycarbonylamino,C1-10 alkylcarbamoyloxy, arylcarbamoyloxy, C1-10 alkylsulfonylamino,arylsulfonylamino, C1-10 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-10 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0049] or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(e) may be further optionallysubstituted by one or more R_(f);

[0050] R_(f) is C1-5 alkyl, C3-6 cycloalkyl, tolylsulfonyl, C1-5 alkoxy,aryl, aryloxy, benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino;

[0051] R₆ is hydrogen, hydroxy, nitrile or a C1-6 saturated orunsaturated branched or unbranched carbon chain optionally partially orfully halogenated wherein one or more C atoms are optionally replaced byO, NH, S(O), S(O)₂ or S and wherein said chain is optionallyindependently substituted with 1-2 oxo groups, —NH₂, one or more C₁₋₄alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl;

[0052] wherein R₁ and R₆ in the formulas (Ia) or (Ib) optionally form a4 to 8 membered mono- or 7-12 membered polycyclo heteroring system, eacharomatic or nonaromatic, wherein each heteroring is optionallysubstituted by one or more R₇;

[0053] each R₇ and R₈ are independently:

[0054] C1-5 alkyl chain optionally interrupted by one or two N, O orS(O)_(m) and optionally substituted by 1-2 oxo, amino, hydroxy, halogen,C1-4alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl,

[0055] aryl, aryloxy, aroyl, furanyl, thienyl, pyrrolyl, imidazolyl,pyridinyl, pyrimidinyl, C1-5 alkanoyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, benzyloxycarbonyl, C1-5 alkanoylamino, aroylamino, C1-5alkylthio, arylthio C1-5 alkylsulfonylamino, arylsulfonylamino, C1-5alkylaminosulfonyl, arylaminosulfonyl, C3-6 cycloalkyl and benzyloxyeach of the aforementioned are optionally halogenated, halogen, hydroxy,oxo, carboxy, nitrile, nitro or NH₂C(O)—;

[0056] m is 0, 1 or 2;

[0057] X is ═O, ═S or ═N—R₆ wherein R₆ is as defined above, and

[0058] pharmaceutically acceptable derivatives thereof.

[0059] In another embodiment of the invention, there are provided novelcompounds of the formula (Ia) and formula (Ib) as described immediatelyabove, and wherein:

[0060] Het is piperidinyl, pyrrolidinyl, tetrahydropyranyl,tetrahydrothiopyranyl, azetidinyl, azepanyl, oxepanyl,tetrahydrofuranyl, oxetanyl, hexahydropyrimidinyl, hexahydropryidazinyl,piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, octahydro-indolizinyl,octahydro-quinolizinyl, decahydro-quinolinyl,1,2,3,4-tetrahydro-quinolinyl, dihydro-oxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide, imidazolidinyl, pyrazolidinyl or a bridgedbicyclo chosen from aza-bicyclo[3.2.1]octane, aza-bicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.2]nonane,aza-bicyclo[2.1.1]hexane, aza-bicyclo[3.1.1]heptane,aza-bicyclo[3.3.2]decane and 2-oxa or2-thia-5-aza-bicyclo[2.2.1]heptane; each ring being substituted with oneor more R₅;

[0061] R₁ is a bond, hydrogen, C1-7 alkyl, C1-7 alkoxy, C3-7 cycloalkyl,aryloxy, phenyl, benzyl, naphthyl, tetrahydronaphthyl,C1-7alkylsulfonylC1-7alkyl, C3-7cycloalkylsulfonylC1-7alkyl,arylsulfonylC1-7alkyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl,thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,isoxazolyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl,benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoisoxazolyl, benzoxazolyl or amino; wherein R₁ is optionallysubstituted by one or more R_(a);

[0062] R_(a) is a bond C1-7 alkyl, C3-6 cycloalkyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl,tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, quinolinyl,isoquinolinyl, quinazolinyl, quinoxalinyl, C1-7 alkoxy, C1-7alkanoyl,C1-7alkanoyloxy, aryloxy, benzyloxy, C1-7 alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-7 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0063] or R_(a) is C1-7 alkanoylamino, aroylamino, C1-7 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

[0064] or R_(a) is C1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

[0065] or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0066] R_(b) is C1-5 alkyl, C3-6 cycloalkyl, aryl, C1-5 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino;

[0067] R₂ is hydrogen or methyl or ethyl;

[0068] R₃ is a bond, hydrogen, C1-5 alkyl, C2-5alkylene, C3-7cycloalkyl, arylC1-3alkyl or aryl wherein R₃ is optionally substitutedby one or more R_(c);

[0069] R_(c) is C1-5 alkyl, C3-7 cycloalkyl, aryl, indanyl, indenyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, tetrahydrofuranyl,pyranyl, tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-5 alkoxy, aryloxy, C1-5 alkanoyl, aroyl, C1-5 alkoxycarbonyl,aryloxycarbonyl, C1-5 alkanoyloxy, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, triazolyl, tetrazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

[0070] or R_(c) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0071] or R_(c) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, indolinyl, furanyl, thienyl, pyrrolyl,oxazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0072] or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoor guanidino, R_(c) may be further optionally substituted by one or moreR_(d);

[0073] R_(c) is C1-5 alkyl, C3-6 cycloalkyl, aryl, arylC1-4 alkyl, C1-5alkoxy, aryloxy, arylC1-5alkoxy, aroyl, halogen, hydroxy, oxo or cyano;

[0074] R₄ is hydrogen or methyl;

[0075] R₅ is a bond, hydrogen, carbonyl, C1-8 alkyl,C1-8alkoxyC1-8alkyl, C1-8alkylaminoC1-8alkyl, C1-8alkylthioC1-8alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-8alkoxy,, aryloxy, C3-7 cycloalkyl, aryl, benzyl, tetrahydronaphthyl,indanyl, heterocyclyl selected from pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, indolinyl, pyranyl,tetrahydropyranyl, thiopyranyl, tetrahydrothiopyranyl, furanyl,tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, tetrazolyl, triazolyl, pyrazolyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl, benzoxazolyl and quinoxalinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-7alkanoyl, aroyl,C1-7alkanoyloxy, benzyloxy, C1-7 alkoxycarbonyl, arylC1-4alkoxycarbonyl,aryloxycarbonyl, aroyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-7 alkyl, aryl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl or quinoxalinyl,

[0076] or R₅ is C1-7 alkanoylamino, aroylamino, C1-7 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, arylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

[0077] or R₅ is C1-7 alkoxycarbonylamino, aryloxycarbonylamino, C1-7alkylcarbamoyloxy, arylcarbamoyloxy, C1-7 alkylsulfonylamino,arylsulfonylamino, C1-7 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-7 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, pyrrolyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl,benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl,isoquinolinyl, quinazolinyl or quinoxalinyl,

[0078] or R₅ is halogen, hydroxy, oxy, oxo, carboxy, cyano, nitro orcarboxamide, R₅ may be further optionally substituted by one or moreR_(e);

[0079] R_(e) is C1-7 alkyl, C1-7alkoxyC1-7alkyl,C1-7alkylaminoC1-7alkyl, C1-7alkylthioC1-7alkyl wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, C1-7 alkoxy, C3-7 cycloalkyl,aryl, tetrahydronaphthyl, indanyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, thiopyranyl,tetrahydrothiopyranyl, tetrahydropyranyl, tetrahydrofuranyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl,benzthiazolyl, benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl,quinoxalinyl, C1-5 alkanoyl, aroyl, C1-5alkanoyloxy, aryloxy, benzyloxy,C1-5 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-5 alkyl,aryl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinylor quinoxalinyl,

[0080] or R_(e) is C1-5 alkanoylamino, aroylamino, C1-5 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

[0081] or R_(e) is C1-5 alkoxycarbonylamino, aryloxycarbonylamino, C1-5alkylcarbamoyloxy, arylcarbamoyloxy, C1-5 alkylsulfonylamino,arylsulfonylamino, C1-5 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl or quinoxalinyl,

[0082] or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(e) may be further optionallysubstituted by one or more R_(f);

[0083] R_(f) is methyl, ethyl, t-butyl, tolylsulfonyl, C1-3 alkoxy,cyclopropyl, cyclohexyl, phenyl, naphthyl, phenoxy, benzyloxy, fluoro,chloro, bromo, hydroxy, oxo, carboxy, cyano, nitro or carboxamide;

[0084] R₆ is hydrogen, hydroxy, nitrile or a C1-6 saturated orunsaturated branched or unbranched carbon chain optionally partially orfully halogenated wherein one or more C atoms are optionally replaced byO, NH, S(O), S(O)₂ or S and wherein said chain is optionallyindependently substituted with 1-2 oxo groups, —NH₂, one or more C1-4alkyl, pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl,piperazinyl, indolinyl, pyranyl, thiopyranyl, furanyl, thienyl,pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzofuranyl, benzothienyl,benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl, quinazolinyl,benzoxazolyl or quinoxalinyl;

[0085] R₁ and R₆ of the formula (Ia) or formula (Ib) form a monocyclic5, 6 or 7 membered aromatic or nonaromatic heterocyclic ring optionallysubstituted by R₇;

[0086] or a bicyclic ring having one 5, 6 or 7 membered aromatic ornonaromatic heterocyclic ring fused to a second 5-7 membered aromatic ornonaromatic heterocyclic or carbocyclic ring wherein each ring isoptionally independently substituted by one or more R₇;

[0087] R₇ and R₈ are independently C1-5 alkyl, C3-6 cycloalkyl, aryl,C1-5 alkoxy, aryloxy, benzyloxy each of the aforementioned areoptionally halogenated or R_(x) is halogen, hydroxy, oxo, carboxy,nitrile, nitro or NH₂C(O)—;

[0088] m is 0, 1 or 2 and

[0089] X is O or S.

[0090] In yet another embodiment of the invention, there are providednovel compounds of the formulas (Ia) and (Ib) as described immediatelyabove, and wherein:

[0091] Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl,octahydro-indolizinyl, octahydro-quinolizinyl oraza-bicyclo[3.2.1]octanyl, each ring being optionally substituted withone or more R₅;

[0092] R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy,phenyl, benzyl, naphthyl, C1-3alkylsulfonylC1-3alkyl,C3-6cycloalkylsulfonylC1-3alkyl, arylsulfonylC1-3alkyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, isoxazolyl,pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl,benzthienyl, benzimidazolyl, benzthiazolyl, benzoxazolyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

[0093] R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy, aryloxy,benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy, carbamoylwherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0094] or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0095] or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0096] or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0097] R_(b) is C1-3 alkyl, C3-6 cycloalkyl, aryl, C1-3 alkoxy, aryloxy,benzyloxy, halogen, hydroxy, oxo, carboxy, cyano, nitro, carboxamide,amidino or guanidino;

[0098] R₂ is hydrogen or methyl;

[0099] R₃ is a bond, hydrogen, C1-5 alkyl, C2-5alkylene, C4-6 cycloalkylor arylC1-2alkyl wherein R₃ is optionally substituted by one or moreR_(c);

[0100] R_(c) is C1-4 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, indolinyl, furanyl, tetrahydrofuranyl, pyranyl,tetrahydropyranyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,pyrazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyl,quinazolinyl, quinoxalinyl, C1-4 alkoxy, phenoxy, naphthyloxy, C1-3alkanoyl, benzoyl, C1-3 alkoxycarbonyl, phenoxycarbonyl, C1-3alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-5 alkyl or aryl,

[0101] or R_(c) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-5 alkyl or aryl,

[0102] or R_(c) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-5 alkyl or aryl,

[0103] or R_(c) is halogen, hydroxy, oxo, carboxy, cyano, nitro, amidinoor guanidino, R_(c) may be further optionally substituted by one or moreR_(d);

[0104] R_(d) is C1-3 alkyl, C3-6 cycloalkyl, phenyl, benzyl, C1-3alkoxy, phenoxy, phenylC1-3alkoxy, benzoyl, halogen, hydroxy, oxo orcyano;

[0105] R₄ is hydrogen;

[0106] R₅ is a bond, hydrogen, carbonyl, C1-6 alkyl,C1-6alkoxyC1-6alkyl, C1-6alkylaminoC1-6alkyl, C1-6alkylthioC1-6alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-6alkoxy, phenoxy, naphthyloxy, C3-6 cycloalkyl, phenyl, naphthyl, benzyl,indanyl, heterocyclyl selected from pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, tetrahydropyranyl,tetrahydrothiopyranyl, furanyl, tetrahydrofuranyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazolyl, benzofuranyl,benzothienyl, benzimidazolyl, benzthiazolyl, quinolinyl, isoquinolinyland benzoxazolyl, heterocyclyloxy wherein the heterocyclyl moiety isselected from those herein described in this paragraph, C1-3alkanoyl,benzoyl, naphthoyl, C1-4alkanoyloxy, benzyloxy, C1-4 alkoxycarbonyl,arylC1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl whereinthe nitrogen atom may be independently mono or di-substituted by C1-3alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0107] or R₅ is C1-4 alkanoylamino, aroylamino, C1-4 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, arylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, indolyl, benzofuranyl, benzothienyl, benzimidazolyl orbenzthiazolyl,

[0108] or R₅ is C1-4 alkoxycarbonylamino, phenoxycarbonylamino, C1-4alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-4 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0109] or R₅ is halogen, hydroxy, oxo, carboxy, cyano, nitro orcarboxamide, R₅ may be further optionally substituted by one or moreR_(e);

[0110] R_(e) is C1-4 alkyl, C1-4 alkoxy, C3-7 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydrothiopyranyl, tetrahydropyranyl,tetrahydrofuranyl, thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, pyrazinyl, indolyl, benzimidazolyl, benzthiazolyl,benzoxazolyl, quinolinyl, isoquinolinyl, quinazolinyl, quinoxalinyl,C1-4 alkanoyl, aroyl, C1-4alkanoyloxy, phenoxy, naphthyloxy, benzyloxy,C1-4 alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl, or benzthiazolyl,

[0111] or R_(e) is C1-4 alkanoylamino, benzoylamino, C1-4 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl,

[0112] or R_(e) is C1-4 alkoxycarbonylamino, phenoxycarbonylamino, C1-4alkylcarbamoyloxy, phenylcarbamoyloxy, C1-4 alkylsulfonylamino,phenylsulfonylamino, C1-4 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0113] or R_(e) is halogen, hydroxy, oxo, carboxy, cyano, nitro orcarboxamide, R_(e) may be further optionally substituted by one or moreR_(f);

[0114] R_(f) is methyl, ethyl, t-butyl, tolylsulfonyl, methoxy,cyclopropyl, phenyl, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy,oxo, carboxy or carboxamide.

[0115] R₁ and R₆ of the formula (Ia) or Formula (Ib) optionally form amonocyclic 5 or 6 membered aromatic or nonaromatic heterocyclic ringoptionally substituted by R₇;

[0116] or a bicyclic ring having one 5, 6 or 7 membered aromatic ornonaromatic heterocyclic ring fused to a second 5-6 membered aromatic ornonaromatic heterocyclic or carbocyclic ring wherein each ring isoptionally independently substituted by one or more R₇;

[0117] R₇ and R₈ are independently C1-4 alkyl, C5-6 cycloalkyl, C1-4alkoxy, halogen, hydroxy, oxo, carboxy, nitrile, nitro or NH₂C(O)—; and

[0118] X is O.

[0119] In yet still another embodiment of the invention, there areprovided novel compounds of the formulas (Ia) and (Ib) as describedimmediately above, and wherein:

[0120] Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

[0121] R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy,phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

[0122] R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclohexyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy,aryloxy, benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or piperazinyl,

[0123] or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0124] or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0125] or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0126] R_(b) is methyl, ethyl, n-propyl, i-propyl, cyclopropyl,cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, i-propoxy,phenoxy, benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy,cyano, nitro or carboxamide;

[0127] R₂ is hydrogen;

[0128] R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzylor naphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0129] R_(c) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, furanyl, tetrahydropyranyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl,benzothienyl, benzthiazolyl, C1-3 alkoxy, phenoxy, naphthyloxy, C1-2alkanoyl, benzoyl, C1-2 alkoxycarbonyl, phenoxycarbonyl,C1-2alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or aryl,

[0130] or R_(e) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl or aryl, or R_(c) is C1-2 alkoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, arylcarbamoyloxy, C1-2alkylsulfonylamino, phenylsulfonylamino, C1-2alkylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or-di-substituted by C1-3 alkyl or phenyl,

[0131] or R_(c) is halogen, hydroxy, oxo, carboxy or cyano, R_(c) may befurther optionally substituted by one or more R_(d);

[0132] R_(d) is methyl, cyclopropyl, cyclohexyl, phenyl, benzyl,methoxy, phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxo or cyano;

[0133] R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl,C1-5alkoxyC1-5alkyl, C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-5alkoxy, phenoxy, C3-6 cycloalkyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-3alkanoyl, benzoyl, naphthoyl,C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0134] or R₅ is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl,

[0135] or R₅ is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0136] or R₅ is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅may be further optionally substituted by one or more R_(e);

[0137] R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl,

[0138] or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0139] or R_(e) is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl or benzthiazolyl,

[0140] or R_(e) is halogen, hydroxy, oxo, carboxy, cyano or carboxamide,R_(e) may be further optionally substituted by one or more R_(f); and

[0141] R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide;

[0142] R₁ and R₆ of the formula (Ia) or Formula (Ib) form a bicyclicring having one 5 or 6 membered aromatic or nonaromatic heterocyclicring fused to a second 5-6 membered heteroaryl, heterocycle or phenylring;

[0143] wherein each ring is optionally independently substituted by oneor two R₇.

[0144] In yet a further embodiment of the invention, there are providednovel compounds of the formulas (Ia) and (Ib) as described immediatelyabove, and wherein:

[0145] Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl ortetrahydropyranyl each ring being substituted with one or more R₅;

[0146] R₁ is a bond, methyl, ethyl, i-propyl, methoxy, ethoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

[0147] R_(a) is a bond, methyl, ethyl, cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy,methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

[0148] or R_(a) is acetylamino, benzoylamino, methylthio, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl,

[0149] or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylearbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

[0150] or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy,cyano, nitro or carboxamide, R_(a) may be further optionally substitutedby one or more R_(b);

[0151] R_(b) is methyl, cyclopropyl, phenyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, hydroxy, oxo, carboxy or carboxamide;

[0152] R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzylor naphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0153] R_(c) is methyl, ethyl, n-propyl, i-propyl, C5-6 cycloalkyl,indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1.]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl,indolyl, benzofuranyl, benzothienyl, benzthiazolyl, methoxy, ethoxy,phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl, ethyl or aryl,

[0154] or R_(c) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or aryl,

[0155] or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl,

[0156] or R_(c) is fluoro, chloro or oxo, R_(c) may be furtheroptionally substituted by one or more R_(d);

[0157] R_(d) is methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro oroxo;

[0158] R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl,C1-4alkoxyC1-4alkyl, C1-4alkylaminoC1-4alkyl, C1-4alkylthioC1-4alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-4alkoxy,phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,benzyl, indanyl, heterocyclyl selected from pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0159] or R₅ is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

[0160] or R₅ is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0161] or R₅ is fluoro, chloro, bromo, hydroxy, oxo, carboxy orcarboxamide, R₅ may be further optionally substituted by one or moreR_(e);

[0162] R_(e) is C1-3 alkyl, C1-2 alkoxy, C3-6 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-2 alkanoyl, aroyl, C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-2 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0163] or R_(e) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl orpyrimidinyl,

[0164] or R_(e) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0165] or R_(e) is fluoro, chloro, bromo, hydroxy, oxo, carboxy orcarboxamide, R_(e) may be further optionally substituted by one or moreR_(f);

[0166] R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, hydroxy, oxo, carboxy or carboxamide and

[0167] R₁ and R₆ of the formula (Ia) or Formula (Ib) form a bicyclicring having one 5-6 membered aromatic or nonaromatic heterocyclic ringfused to a phenyl ring;

[0168] wherein each ring is optionally independently substituted by oneor two R₇.

[0169] In yet still a further embodiment of the invention, there areprovided novel compounds of the formula (Ia) or formula (Ib) asdescribed immediately above, and wherein:

[0170] Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl,azetidin-3-yl, azepan-3-yl, azepan-4-yl or tetrahydropyran-4-yl, eachring being optionally substituted with one or more R₅;

[0171] R₁ is a bond, methyl, ethyl, i-propyl, methoxy, cyclopropyl,cyclohexyl, phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino; whereinR₁ is optionally substituted by one or more R_(a);

[0172] R_(a) is methyl, phenyl, thienyl, methoxy, acetyl, acetoxy,phenoxy, benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl orphenyl,

[0173] or R_(a) is acetylamino, methylthio, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl orphenyl,

[0174] or R_(a) is methoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

[0175] or R_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano orcarboxamide;

[0176] R₃ is a bond, methyl, ethyl, n-propyl, propenyl, butenyl,i-butenyl, cyclohexyl, benzyl or naphthylmethyl wherein R₃ is optionallysubstituted by one or more R_(c);

[0177] R_(c) is methyl, ethyl, n-propyl, i-propyl, cyclohexyl,cyclopentyl, indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, fluoro, chloro or oxo;

[0178] R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl,C1-2alkoxyC1-2alkyl, C1-2alkylaminoC1-2alkyl, C1-2alkylthioC1-2alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-2alkoxy, phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,tetrahydropyranyl, pyridinyl, and pyrimidinyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from those herein described in thisparagraph, acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

[0179] or R₅ is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor phenyl,

[0180] or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

[0181] or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅may be further optionally substituted by one or more R_(e);

[0182] R_(e) is methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, indanyl, piperidinyl, morpholinyl,indolyl, thienyl, pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy,benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

[0183] or R_(e) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl,

[0184] or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

[0185] or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide,R_(e) may be further optionally substituted by one or more R_(f); and

[0186] R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy,fluoro, chloro or oxo;

[0187] R₁ and R₆ of the formula (Ia) or Formula (Ib) form the bicyclicring

[0188]  wherein W is —S(O)_(n)—, —O—C(O)— or —N—C(O)—, n is 0, 1 or 2and wherein each ring is optionally independently substituted by one ortwo R₇.

[0189] In a further embodiment of the invention, there are providednovel compounds of the formulas (Ia) and (Ib) as described immediatelyabove, and wherein:

[0190] Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl,azetidin-3-yl or tetrahydropyran-4-yl, each ring being substituted withone or more R₅;

[0191] R₁ is i-propyl, benzyloxy, cyclohexyl, phenyl,4-(acetylamino)-phenyl, 4-(methanesulfonylamino)-phenyl,4-methoxyphenyl, 3-phenoxyphenyl, 4-chlorophenyl, 4-fluorophenyl,2-fluorophenyl, 2-fluoro-4-chlorophenyl, naphthyl, thienylmethyl,piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, furanyl, thienyl,5-chlorothienyl, pyridin-4-yl, pyrazinyl, methylamino, ethylamino,dimethylamino or diethylamino;

[0192] R₃ is ethyl, n-propyl,propenyl, butenyl, i-butenyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0193] R_(c) is methyl, cyclohexyl, cyclopentyl, indanyl,1,2,3,4-tetrahydronaphthyl, methoxy, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, fluoro or chloro;

[0194] R₅ is a bond, carbonyl, methyl, ethyl, n-propyl, n-butyl,t-butyl, i-propyl, i-butyl, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, benzyl, piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl,benzoyl, ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy,R₅ may be further optionally substituted by one or more R_(e);

[0195] R_(e) is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,naphthyl, indanyl, thienyl, 5-methylthienyl, methoxy, phenoxy,benzyloxy, piperidinyl, pyridinyl, indolyl, 1-(tolyl-sulfonyl)-indolyl,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, phenyl or benzyl,

[0196] or R_(e) is hydroxy, fluoro, chloro, oxo, dimethylamino ortrifluoromethyl; and

[0197] n is 2.

[0198] In another embodiment of the invention, there are provided novelcompounds of the formulas (Ia) and (Ib) as described for the broadestgeneric aspect above and wherein:

[0199] R₁ and R₆ remain acyclic,

[0200] Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

[0201] R₁ is a bond, C1-5 alkyl, C1-5 alkoxy, C3-6 cycloalkyl, aryloxy,phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

[0202] R_(a) is a bond, C1-3 alkyl, cyclopropyl, cyclohexyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, C1-3 alkoxy, C1-3alkanoyl, C1-3alkanoyloxy,aryloxy, benzyloxy, C1-3 alkoxycarbonyl, aryloxycarbonyl, aroyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl,morpholinyl, thiomorpholinyl or piperazinyl,

[0203] or R_(a) is C1-3 alkanoylamino, aroylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,arylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0204] or R_(a) is C1-3 alkoxycarbonylamino, aryloxycarbonylamino, C1-3alkylcarbamoyloxy, arylcarbamoyloxy, C1-3 alkylsulfonylamino,arylsulfonylamino, C1-3 alkylaminosulfonyl, arylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, aryl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0205] or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0206] R_(b) is methyl, ethyl, n-propyl, i-propyl, cyclopropyl,cyclopentyl, cyclohexyl, phenyl, methoxy, ethoxy, n-propoxy, i-propoxy,phenoxy, benzyloxy, fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy,cyano, nitro or carboxamide;

[0207] R₂ is hydrogen;

[0208] R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzylor naphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0209] R_(c) is C1-3 alkyl, C5-6 cycloalkyl, phenyl, naphthyl, indanyl,bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[4.1.0]heptanyl,bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,1,2,3,4-tetrahydronaphthyl, furanyl, tetrahydropyranyl, thienyl,oxazolyl, thiazolyl, imidazolyl, pyrimidinyl, indolyl, benzofuranyl,benzothienyl, benzthiazolyl, C1-3 alkoxy, phenoxy, naphthyloxy, C1-2alkanoyl, benzoyl, C1-2 alkoxycarbonyl, phenoxycarbonyl,C1-2alkanoyloxy, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl or aryl,

[0210] or R_(c) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl or aryl,

[0211] or R_(c) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, arylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl or phenyl,

[0212] or R_(c) is halogen, hydroxy, oxo, carboxy or cyano, R_(c) may befurther optionally substituted by one or more R_(d);

[0213] R_(d) is methyl, cyclopropyl, cyclohexyl, phenyl, benzyl,methoxy, phenoxy, benzyloxy, benzoyl, fluoro, chloro, oxo or cyano;

[0214] R₄ is hydrogen;

[0215] R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl,C1-5alkoxyC1-5alkyl, C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-5alkoxy, phenoxy, C3-6 cycloalkyl, phenyl, naphthyl, benzyl, indanyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-3alkanoyl, benzoyl, naphthoyl,C1-3alkanoyloxy, benzyloxy, C1-3 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-3 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0216] or R₅ is C1-3 alkanoylamino, aroylamino, C1-3 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzofuranyl,benzothienyl, benzimidazolyl or benzthiazolyl,

[0217] or R₅ is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0218] or R₅ is halogen, hydroxy, oxo, carboxy, cyano or carboxamide, R₅may be further optionally substituted by one or more R_(e);

[0219] R_(e) is C1-3 alkyl, C1-3 alkoxy, C3-7 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-3 alkanoyl, aroyl, C1-3alkanoyloxy, phenoxy, benzyloxy, C1-3alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-3 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl orbenzthiazolyl,

[0220] or R_(e) is C1-3 alkanoylamino, benzoylamino, C1-3 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-3 alkyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl,pyrimidinyl, benzimidazolyl or benzthiazolyl,

[0221] or R_(e) is C1-3 alkoxycarbonylamino, phenoxycarbonylamino, C1-3alkylcarbamoyloxy, phenylcarbamoyloxy, C1-3 alkylsulfonylamino,phenylsulfonylamino, C1-3 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-3 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,benzimidazolyl or benzthiazolyl,

[0222] or R_(e) is halogen, hydroxy, oxo, carboxy, cyano or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

[0223] R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, bromo, hydroxy, oxo, carboxy or carboxamide;

[0224] R₆ is hydroxy, nitrile or a C1-5 saturated or unsaturatedbranched or unbranched carbon chain optionally partially or fullyhalogenated wherein one or more C atoms are optionally replaced by O,NH, or S(O)₂ and wherein said chain is optionally independentlysubstituted with 1-2 oxo groups, —NH₂, one or more C1-4 alkyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,indolinyl, pyranyl, thiopyranyl, furanyl, thienyl, pyrrolyl, oxazolyl,isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl,indolyl, benzofuranyl, benzothienyl, benzimidazolyl, benzthiazolyl,quinolinyl, isoquinolinyl, quinazolinyl, benzoxazolyl or quinoxalinyl;and

[0225] X is O.

[0226] In another embodiment of the invention, there are provided novelcompounds of the formula (Ia) and (Ib) as described immediately above,and wherein:

[0227] R₁ is a bond, methyl, ethyl, i-propyl, methoxy, ethoxy,cyclopropyl, cyclopentyl, cyclohexyl, phenoxy, phenyl, benzyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,furanyl, thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino;wherein R₁ is optionally substituted by one or more R_(a);

[0228] R_(a) is a bond, methyl, ethyl, cyclopropyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,thienyl, imidazolyl, methoxy, acetyl, acetoxy, phenoxy, benzyloxy,methoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

[0229] or R_(a) is acetylamino, benzoylamino, methylthio, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl,

[0230] or R_(a) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

[0231] or R_(a) is fluoro, chloro, bromo, iodo, hydroxy, oxo, carboxy,cyano, nitro or carboxamide, R_(a) may be further optionally substitutedby one or more R_(b);

[0232] R_(b) is methyl, cyclopropyl, phenyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, hydroxy, oxo, carboxy or carboxamide;

[0233] R₃ is a bond, C1-3 alkyl, C2-4alkylene, C5-6 cycloalkyl, benzylor naphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0234] R_(c) is methyl, ethyl, n-propyl, i-propyl, C5-6 cycloalkyl,indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, thienyl, oxazolyl, thiazolyl,indolyl, benzofuranyl, benzothienyl, benzthiazolyl, methoxy, ethoxy,phenoxy, acetyl, benzoyl, methoxycarbonyl, phenoxycarbonyl, acetoxy,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl, ethyl or aryl,

[0235] or R_(c) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or aryl,

[0236] or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl, ethyl or phenyl,

[0237] or R_(c) is fluoro, chloro or oxo, R_(c) may be furtheroptionally substituted by one or more R_(d);

[0238] R_(d) is methyl, cyclopropyl, phenyl, methoxy, fluoro, chloro oroxo;

[0239] R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl,C1-4alkoxyC1-4alkyl, C1-4alkylaminoC1-4alkyl, C1-4alkylthioC1-4alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-4alkoxy,phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, naphthyl,benzyl, indanyl, heterocyclyl selected from pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, tetrahydropyranyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, benzimidazolyl and benzthiazolyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, C1-2alkanoyl, benzoyl, naphthoyl,C1-2alkanoyloxy, benzyloxy, C1-2 alkoxycarbonyl, benzyloxycarbonyl,phenoxycarbonyl, benzoyloxy, carbamoyl wherein the nitrogen atom may beindependently mono or di-substituted by C1-2 alkyl, phenyl,pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0240] or R₅ is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl, benzimidazolylor benzthiazolyl,

[0241] or R₅ is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0242] or R₅ is fluoro, chloro, bromo, hydroxy, oxo, carboxy orcarboxamide, R₅ may be further optionally substituted by one or moreR_(e);

[0243] R_(e) is C1-3 alkyl, C1-2 alkoxy, C3-6 cycloalkyl, phenyl,naphthyl, indanyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl,tetrahydropyranyl, indolyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyridinyl, pyrimidinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl,C1-2 alkanoyl, aroyl, C1-2alkanoyloxy, phenoxy, benzyloxy, C1-2alkoxycarbonyl, phenoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by C1-2 alkyl,phenyl, pyrrolidinyl, piperidinyl, morpholinyl, piperazinyl, oxazolyl,thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0244] or R_(e) is C1-2 alkanoylamino, benzoylamino, C1-2 alkylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by C1-2 alkyl, phenyl, pyrrolidinyl, piperidinyl,morpholinyl, piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl orpyrimidinyl,

[0245] or R_(e) is C1-2 alkoxycarbonylamino, phenoxycarbonylamino, C1-2alkylcarbamoyloxy, phenylcarbamoyloxy, C1-2 alkylsulfonylamino,phenylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted byC1-2 alkyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,piperazinyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl or pyrimidinyl,

[0246] or R_(e) is fluoro, chloro, bromo, hydroxy, oxo, carboxy orcarboxamide, R_(e) may be further optionally substituted by one or moreR_(f);

[0247] R_(f) is methyl, phenyl, tolylsulfonyl, methoxy, phenoxy,benzyloxy, fluoro, chloro, hydroxy, oxo, carboxy or carboxamide and

[0248] R₆ is nitrile or a C1-5 saturated or unsaturated branched orunbranched carbon chain optionally partially or fully halogenatedwherein one or more C atoms are optionally replaced by O, NH, or S(O)₂and wherein said chain is optionally independently substituted with oxo,—NH₂, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, pyridinyl,pyrimidinyl or pyrazinyl.

[0249] In yet another embodiment of the invention, there are providednovel compounds of the formula (Ia) or formula (Ib) as describedimmediately above, and wherein:

[0250] Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl,azetidin-3-yl, azepan-3-yl, azepan-4-yl or tetrahydropyran-4-yl, eachring being optionally substituted with one or more R₅;

[0251] R₁ is a bond, methyl, ethyl, i-propyl, methoxy, cyclopropyl,cyclohexyl, phenoxy, phenyl, benzyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, thiazolyl, imidazolyl, pyridinyl, pyrazinyl or amino; whereinR₁ is optionally substituted by one or more R_(a);

[0252] R_(a) is methyl, phenyl, thienyl, methoxy, acetyl, acetoxy,phenoxy, benzyloxy, methoxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl orphenyl,

[0253] or R_(a) is acetylamino, methylthio, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl orphenyl,

[0254] or R_(a) is methoxycarbonylamino, methylcarbamoyloxy,phenylcarbamoyloxy, methylsulfonylamino, phenylsulfonylamino, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

[0255] or R_(a) is fluoro, chloro, hydroxy, oxo, carboxy, cyano orcarboxamide;

[0256] R₃ is a bond, methyl, ethyl, n-propyl, propenyl, butenyl,i-butenyl, cyclohexyl, benzyl or naphthylmethyl wherein R₃ is optionallysubstituted by one or more R_(c);

[0257] R_(c) is methyl, ethyl, n-propyl, i-propyl, cyclohexyl,cyclopentyl, indanyl, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl,bicyclo[4.1.0]heptanyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl,cubanyl, 1,2,3,4-tetrahydronaphthyl, methoxy, phenoxy, acetyl, benzoyl,methoxycarbonyl, phenoxycarbonyl, acetoxy, benzoyloxy, methylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,phenylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, fluoro, chloro or oxo; and

[0258] wherein the configuration at the stereocenter defined by R₂ andR₃ when they are different and the carbon they are attached to isdefined as L; and

[0259] R₅ is a bond, hydrogen, carbonyl, C1-4 alkyl,C1-2alkoxyC1-2alkyl, C1-2alkylaminoC1-2alkyl, C1-2alkylthioC1-2alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-2alkoxy, phenoxy, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, benzyl,heterocyclyl selected from pyrrolidinyl, piperidinyl, morpholinyl,tetrahydropyranyl, pyridinyl, and pyrimidinyl, heterocyclyloxy whereinthe heterocyclyl moiety is selected from those herein described in thisparagraph, acetyl, benzoyl, acetyloxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, benzyloxycarbonyl, benzoyloxy, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

[0260] or R₅ is acetylamino, benzoylamino, methylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, phenylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ureido whereineither nitrogen atom may be independently substituted by methyl, ethylor phenyl,

[0261] or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

[0262] or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅may be further optionally substituted by one or more R_(e);

[0263] R_(e) is methyl, methoxy, ethoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, indanyl, piperidinyl, morpholinyl,indolyl, thienyl, pyridinyl, acetyl, benzoyl, acetyloxy, phenoxy,benzyloxy, methoxycarbonyl, ethoxycarbonyl, carbamoyl wherein thenitrogen atom may be independently mono or di-substituted by methyl,ethyl or phenyl,

[0264] or R_(e) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl or phenyl,

[0265] or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

[0266] or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

[0267] R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy,fluoro, chloro or oxo;

[0268] R₆ is nitrile or a C1-5 saturated or unsaturated branched orunbranched carbon chain optionally partially or fully halogenatedwherein one or more C atoms are optionally replaced by O, NH, or S(O)₂and wherein said chain is optionally independently substituted with oxo,—NH₂, morpholinyl or piperazinyl.

[0269] In yet still another embodiment of the invention, there areprovided novel compounds of the formulas (Ia) and (Ib) as describedimmediately above, and wherein:

[0270] Het is piperidin-4-yl, piperidin-3-yl, pyrrolidin-3-yl,azetidin-3-yl or tetrahydropyran-4-yl, each ring being substituted withone or more R₅;

[0271] R₁ is i-propyl, benzyloxy, cyclohexyl, phenyl,4-(acetylamino)-phenyl, 4-(methanesulfonylamino)-phenyl,4-methoxyphenyl, 3-phenoxyphenyl, 4-chlorophenyl, 4-fluorophenyl,2-fluorophenyl, 2-fluoro-4-chlorophenyl, naphthyl, thienylmethyl,piperidinyl, morpholinyl, pyrrolidinyl, piperazinyl, furanyl, thienyl,5-chlorothienyl, pyridin-4-yl, pyrazinyl, methylamino, ethylamino,dimethylamino or diethylamino;

[0272] R₃ is ethyl, n-propyl,propenyl, butenyl, i-butenyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0273] R_(c) is methyl, cyclohexyl, cyclopentyl, indanyl,1,2,3,4-tetrahydronaphthyl, methoxy, methylthio wherein the sulfur atommay be oxidized to a sulfoxide or sulfone, fluoro or chloro;

[0274] R₅ is a bond, carbonyl, methyl, ethyl, n-propyl, n-butyl,t-butyl, i-propyl, i-butyl, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, benzyl, piperidinyl, tetrahydropyranyl, pyrimidinyl, acetyl,benzoyl, ethoxycarbonyl, benzyloxycarbonyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy,R₅ may be further optionally substituted by one or more R_(e);

[0275] R_(e) is methyl, cyclopropyl, cyclopentyl, cyclohexyl, phenyl,naphthyl, indanyl, thienyl, 5-methylthienyl, methoxy, phenoxy,benzyloxy, piperidinyl, pyridinyl, indolyl, 1-(tolyl-sulfonyl)-indolyl,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, phenyl or benzyl,

[0276] or R_(e) is hydroxy, fluoro, chloro, oxo, dimethylamino ortrifluoromethyl; and

[0277] R₆ is acetyl, C1-3alkylaminocarbonyl or C1-3alkoxycarbonyl.

[0278] In yet a further embodiment of the invention, there are providednovel compounds of the formulas (Ia) and (Ib) as described immediatelyabove, and wherein:

[0279] Het is piperidin-4-yl or pyrrolidin-3-yl;

[0280] R₁ is morpholin-4-yl, p-fluorophenyl or p-methoxyphenyl;

[0281] R₅ is methyl, propyl, n-pentyl or cyclohexyl and

[0282] R₆ is acetyl, ethylaminocarbonyl or ethoxycarbonyl.

[0283] The activity of particular compounds disclosed herein againstcathepsin K may be determined without undue experimentation by one ofordinary skill in the art in view of the art, the guidance providedthroughout this specification and by the screens described in thesection entitled “Assessment of Biological Properties.”

[0284] The following subgeneric aspect of the compounds of the formulas(Ia) and (Ib) is postulated to possess Cathepsin K activity:

[0285] The broadest embodiment of the formula (Ia) and (Ib) as describedhereinabove and wherein

[0286] Het is piperidinyl, pyrrolidinyl, azetidinyl, azepanyl, oxepanyl,tetrahydropyranyl, oxetanyl or tetrahydrothiopyranyl each ring beingoptionally substituted with one or more R₅;

[0287] R₁ is a bond, C1-4 alkyl, C1-4 alkoxy, cyclopropyl, cyclohexyl,phenoxy, naphthyloxy, phenyl, benzyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, furanyl,thienyl, oxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,pyrazinyl, pyridazinyl, indolyl, quinolinyl, benzofuranyl, benzthienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl or amino; wherein R₁ isoptionally substituted by one or more R_(a);

[0288] R_(a) is methyl, ethyl, propyl, i-propyl, cyclopropyl,cyclohexyl, phenyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, thienyl, imidazolyl, methoxy, ethoxy,acetyl, acetoxy, phenoxy, naphthyloxy, benzyloxy, methoxycarbonyl,ethoxycarbonyl, phenoxycarbonyl, naphthyloxycarbonyl, benzoyloxy,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl, phenyl, naphthyl, pyrrolidinyl,piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

[0289] or R_(a) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, ethylthio whereinthe sulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl, ethyl, phenyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl or piperazinyl,

[0290] or R_(a) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, C1-2 alkylcarbamoyloxy, phenylcarbamoyloxy,naphthylcarbamoyloxy, C1-2 alkylsulfonylamino, phenylsulfonylamino,naphthylsulfonylamino, C1-2 alkylaminosulfonyl, phenylaminosulfonyl,naphthylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or piperazinyl,

[0291] or R_(a) is halogen, hydroxy, oxo, carboxy, cyano, nitro,carboxamide, amidino or guanidino, R_(a) may be further optionallysubstituted by one or more R_(b);

[0292] R_(b) is methyl, ethyl, cyclopropyl, cyclohexyl, phenyl, methoxy,ethoxy, phenoxy, benzyloxy, fluoro, chloro, bromo, hydroxy, oxo,carboxy, cyano, nitro or carboxamide;

[0293] R₂ is hydrogen or methyl;

[0294] R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, n-pentyl, propenyl, i-butenyl, cyclohexyl, benzyl ornaphthylmethyl wherein R₃ is optionally substituted by one or moreR_(c);

[0295] R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl,naphthyl, bicyclo[3.1.0]hexanyl, bicyclo[1.1.1]pentanyl, cubanyl,furanyl, tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, imidazolyl,pyrimidinyl, methoxy, ethoxy, phenoxy, acetyl, benzoyl, methoxycarbonyl,phenoxycarbonyl, acetoxy, benzoyloxy, carbamoyl wherein the nitrogenatom may be independently mono or di-substituted by methyl or phenyl,

[0296] or R_(c) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiowherein the sulfur atom may be oxidized to a sulfoxide or sulfone,ureido wherein either nitrogen atom may be independently substituted bymethyl or phenyl,

[0297] or R_(c) is methoxycarbonylamino, phenoxycarbonylamino,methylcarbamoyloxy, phenylcarbamoyloxy, methylsulfonylamino,phenylsulfonylamino, methylaminosulfonyl, phenylaminosulfonyl, aminowherein the nitrogen atom may be independently mono or di-substituted bymethyl or phenyl,

[0298] or R_(c) is chloro, fluoro, hydroxy, oxo, carboxy or cyano;

[0299] R₂ and R₃ together with the carbon they are attached optionallyform a ring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,pyrrolidinyl, piperidinyl, piperazinyl, morpholinyl ortetrahydrothiophenyl;

[0300] R₄ is hydrogen;

[0301] R₅ is a bond, hydrogen, carbonyl, C1-5 alkyl,C1-5alkoxyC1-5alkyl, C1-5alkylaminoC1-5alkyl, C1-5alkylthioC1-5alkylwherein the sulfur atom may be oxidized to a sulfoxide or sulfone, C1-5alkoxy, phenoxy, naphthyloxy, cyclopropyl, cyclopentyl, cyclohexyl,phenyl, benzyl, heterocyclyl selected from pyrrolidinyl, piperidinyl,morpholinyl, tetrahydropyranyl, pyridinyl, and pyrimidinyl,heterocyclyloxy wherein the heterocyclyl moiety is selected from thoseherein described in this paragraph, acetyl, benzoyl, acetyloxy,benzyloxy, methoxycarbonyl, ethoxycarbonyl, benzyloxycarbonyl,benzoyloxy, carbamoyl wherein the nitrogen atom may be independentlymono or di-substituted by methyl, ethyl or phenyl,

[0302] or R₅ is acetylamino, benzoylamino, phenylthio wherein the sulfuratom may be oxidized to a sulfoxide or sulfone, ureido wherein eithernitrogen atom may be independently substituted by methyl, ethyl orphenyl,

[0303] or R₅ is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,phenylsulfonylamino, phenylaminosulfonyl, amino wherein the nitrogenatom may be independently mono or di-substituted by methyl, ethyl orphenyl,

[0304] or R₅ is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide, R₅may be further optionally substituted by one or more R_(e);

[0305] R_(e) is methyl ethyl, methoxy, ethoxy, cyclopropyl, cyclopentyl,cyclohexyl, phenyl, naphthyl, indanyl, piperidinyl, morpholinyl,indolyl, thienyl, pyridinyl, methoxy, ethoxy, acetyl, benzoyl,acetyloxy, phenoxy, benzyloxy, methoxycarbonyl, ethoxycarbonyl,carbamoyl wherein the nitrogen atom may be independently mono ordi-substituted by methyl, ethyl or phenyl,

[0306] or R_(e) is acetylamino, benzoylamino, methylthio wherein thesulfur atom may be oxidized to a sulfoxide or sulfone, phenylthiomethylthio wherein the sulfur atom may be oxidized to a sulfoxide orsulfone, ureido wherein either nitrogen atom may be independentlysubstituted by methyl, ethyl or phenyl,

[0307] or R_(e) is methoxycarbonylamino, ethoxycarbonylamino,phenoxycarbonylamino, methylcarbamoyloxy, phenylcarbamoyloxy,methylsulfonylamino, phenylsulfonylamino, methylaminosulfonyl,phenylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl, ethyl or phenyl,

[0308] or R_(e) is fluoro, chloro, hydroxy, oxo, carboxy or carboxamide,R_(e) may be further optionally substituted by one or more R_(f);

[0309] R_(f) is methyl, phenyl, tolylsulfonyl, phenoxy, benzyloxy,fluoro, chloro or oxo.

[0310] Preferred cathepsin K inhibitors are those as describedimmediately above and wherein:

[0311] R₁ is a bond, methyl, ethyl, n-propyl, i-propyl, methoxy, ethoxy,benzyloxy, cyclopropyl, cyclohexyl, phenoxy, naphthyloxy, phenyl,benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl,quinolinyl, benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl,benzoxazolyl or amino; wherein R₁ is optionally substituted by one ormore R_(a);

[0312] R_(a) is methyl, cyclopropyl, phenyl, halogen, hydroxy, oxo,carboxy, cyano, nitro or carboxamide;

[0313] R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, n-pentyl, propenyl, i-butenyl, benzyl or naphthylmethyl whereinR₃ is optionally substituted by one or more R_(c);

[0314] R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, carbamoyl wherein the nitrogen atommay be independently mono or di-substituted by methyl or phenyl,

[0315] or R_(c) is acetylamino, benzoylamino, methylthio,methoxycarbonylamino, methylcarbamoyloxy, methylsulfonylamino,methylaminosulfonyl, amino wherein the nitrogen atom may beindependently mono or di-substituted by methyl,

[0316] or R_(c) is fluoro or oxo;

[0317] R₂ and R₃ together with the carbon they are attached optionallyform a ring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,pyrrolidinyl or piperidinyl;

[0318] R₅ is methyl, ethyl, n-propyl, n-butyl, n-pentyl, 2-pentyl,3-pentyl, phenethyl, phenpropyl, 2,2-dimethylpropyl, t-butyl, i-propyl,i-butyl, cyclopropyl, cyclopentyl, cyclohexyl, cyclopropylmethyl,cyclopentylmethyl, cyclohexylmethyl, phenyl, benzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 2,6-dimethylbenzyl, 2,5-dimethylbenzyl,2,4-dimethylbenzyl, 2,3-dimethylbenzyl, 3,4-dimethylbenzyl,3,5-dimethylbenzyl, 2,4,6-trimethylbenzyl, 2-methoxybenzyl,3-methoxybenzyl, 4-methoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,4-phenoxybenzyl, 2-benzyloxybenzyl, 3-benzyloxybenzyl,4-benzyloxybenzyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2,6-difluorobenzyl, 2,5-difluorobenzyl, 2,4-difluorobenzyl,2,3-difluorobenzyl, 3,4-difluorobenzyl, 3,5-difluorobenzyl,2,4,6-triflurobenzyl, 2-trifluoromethylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, naphthylmethyl, indanylmethyl, pyridinylmethyl,indolylmethyl, thienylmethyl, 5-methylthienylmethyl, piperidinyl,piperidinylcarbonyl, pyridinylcarbonyl, tetrahydropyranyl, pyrimidinyl,acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl, t-butoxycarbonyl,methylcarbamoyl, phenylcarbamoyl, benzylcarbamoyl, methylsulfonylamino,phenylsulfonylamino, methylamino, dimethylamino, fluoro, oxo or carboxy.

[0319] Most preferred cathepsin K inhibitors are those as describedimmediately above and wherein:

[0320] R₁ is methoxy, benzyloxy, cyclohexyl, phenoxy, naphthyloxy,phenyl, benzyl, naphthyl, pyrrolidinyl, piperidinyl, morpholinyl,thiomorpholinyl, piperazinyl, furanyl, thienyl, oxazolyl, thiazolyl,imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl, indolyl, quinolinyl,benzofuranyl, benzthienyl, benzimidazolyl, benzthiazolyl, benzoxazolylor amino; wherein R₁ is optionally substituted by one or more R_(a);

[0321] R_(a) is methyl, phenyl, fluoro, chloro, hydroxy, oxo, carboxy orcarboxamide;

[0322] R₃ is a bond, methyl, ethyl, n-propyl, i-propyl, n-butyl,i-butyl, n-pentyl, propenyl, i-butenyl or benzyl wherein R₃ isoptionally substituted by one or more R_(c);

[0323] R_(c) is methyl, ethyl, cyclohexyl, cyclopentyl, phenyl, furanyl,tetrahydropyranyl, thienyl, oxazolyl, thiazolyl, methoxy, phenoxy,acetyl, benzoyl, methoxycarbonyl, acetylamino, methylthio,methylsulfonylamino or fluoro;

[0324] R₂ and R₃ together with the carbon they are attached optionallyform a ring selected from cyclopentyl, cyclohexyl, cycloheptyl,tetrahydropyranyl, tetrahydrothiopyranyl or tetrahydrofuranyl;

[0325] R₅ is methyl, ethyl, n-propyl, n-butyl, phenethyl, phenpropyl,t-butyl, i-propyl, i-butyl, cyclopropyl, cyclohexyl, cyclopropylmethyl,cyclohexylmethyl, phenyl, benzyl, 2-methoxybenzyl, 3-methoxybenzyl,4-methoxybenzyl 4-fluorobenzyl, 3,5-difluorobenzyl,4-trifluoromethylbenzyl, naphthylmethyl, pyridinylmethyl, indolylmethyl,thienylmethyl, acetyl, benzoyl, ethoxycarbonyl, benzyloxycarbonyl,t-butoxycarbonyl, phenylcarbamoyl, phenylsulfonylamino or fluoro.

[0326] Most preferred cathepsin K inhibitors are those as describedimmediately above and wherein:

[0327] Het is pyrrolidinyl, piperidinyl or tetrahydropyranyl;

[0328] R₁ is benzyloxy, phenoxy, naphthyloxy, phenyl, naphthyl,pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl,pyridinyl, indolyl, quinolinyl, benzofuranyl, benzthienyl,benzimidazolyl, benzthiazolyl, benzoxazolyl or phenylamino;

[0329] R₃ is n-propyl, i-butyl, propenyl, i-butenyl or2,2-dimethylpropyl;

[0330] R₂ and R₃ together with the carbon they are attached optionallyform a ring selected from cyclopentyl, cyclohexyl, or cycloheptyl;

[0331] R₅ is methyl, ethyl, n-propyl, phenethyl, t-butyl, i-propyl,i-butyl, cyclohexyl, cyclohexylmethyl, benzyl, 4-fluorobenzyl,naphthylmethyl, acetyl, benzoyl or benzyloxycarbonyl.

[0332] Further compounds of Formula (Ia), made up of components A, B,and C are provided in the following Table I. Any and all combinations ofA, B, and C components within the structural limitations of Formula(Ia), comprise a compound of the invention, and their pharmaceuticallyacceptable derivatives. These compounds can be synthesized by theGeneral schemes, methods described in the experimental section of thisdocument and analogous methods known to those skilled in the art withoutundue experimentation. Preferred compounds will possess desirableinhibition activity of Cathepsin S in a cell based assay as described inRiese, R. J. et al., Immunity, 1996, 4, 357-366, incorporated herein byreference.

TABLE I A

B

C

A1

B1

C1

A2

B2

C2

A3

B3

C3

A4

B4

C4

A5

B5

C5

A6

B6

C6

A7

B7

C7

A8

B8

C8

A9

B9

C9

A10

B10

C10

A11

B11

C11

A12

B12

C12

A13

B13

C13

A14

B14

C14

A15

B15

C15

A16

B16

C16

A17

B17

C17

A18

B18

C18

A19

B19

C19

A20

B20

C20

A21

B21

C21

A22

B22

C22

A23

B23

C23

A24

B24

C24

A25

B25

C25

A26

B26

C26

A27

B27

C27

A28

B28

C28

A29

B29

C29

A30

B30

C30

A31

B31

C31

A32

B32

C32

A33

B33

C33

A34

B34

C34

A35

B35

C35

A36

B35

C36

A37

B37

C37

A38

B38

C38

A39

B39

C39

A40

B40

C40

A41

B41

C41

A42

B42

C42

A43

B43

C43

A44

B44

C44

A45

B45

C45

A46

B46

C46

A47

B47

C47

A48

B48

C48

A49

B49

A50

A51

A52

A53

A54

A55

A56

A57

[0333] and the pharmaceutically acceptable derivates thereof.

[0334] In another embodiment of the invention there are provided thefollowing compounds of the Formulas (Ia) and (Ib) which have beensynthesized using the General schemes, methods described in theexperimental section of this document and analogous methods known tothose skilled in the art without undue experimentation. The compoundpossess desirable inhibition activity of Cathepsin S in the cell basedassay referenced above.

[0335] {[1-(3-cyano-1-isobutyl-piperdin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 493 (M+1)

[0336]N-(2Cyano-octahydro-quinolizin-2-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ-benzo-3-ylamino)-propionamide;MS: 498 (M+1)

[0337]{[1-3-Cyano-1-methyl-piperidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 451 (M+1)

[0338]{[1-(2-cyano-octahydro-quinolizin-2-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 491 (M+1)

[0339]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-methyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 465 (M+1)

[0340]{[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 545 (M+1)

[0341]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexylmethyl ester; MS: 545 (M+1)

[0342]{[-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclobutyl ester; MS: 503 (M+1)

[0343]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid allyl ester; MS: 489 (M+1)

[0344]N-(4-Cyano-1-propyl-piperidin-4-yl)-4-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 480 (M+1)

[0345]{[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-3-cyclohexyl-propylamino]-morpholin-4-yl-methylene}-carbamicacid ester; MS: 519 (M+1)

[0346]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid tetrahydro-furan-3ylmethyl ester; MS: 533 (M+1)

[0347]{[1-(4-cyano-1-methy-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4yl-methylene}-carbamicacid tetrahydro-furan-2-ylmethyl ester; MS: 533 (M+1)

[0348]N-(4-Cyano-1-methy-piperidin-4-yl)-3-cyclohexyl-2-(5,6-difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;MS: 458 (M+1)

[0349]2-(5,6-Difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 460 (M+1)

[0350]2-(6-Fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 442 (M+1)

[0351]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(6-fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;MS: 440 (M+1)

[0352]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 465 (M+1)

[0353]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 463 (M+1)

[0354]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2,2-dimethyl-propyl ester; MS: 519 (M+1)

[0355]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 437 (M+1)

[0356]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid benzyl ester; MS: 539 (M+1)

[0357]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid isobutyl ester; MS: 505 (M+1)

[0358]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid propyl ester; MS: 491 (M+1)

[0359]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid hexyl ester; MS: 533 (M+1)

[0360]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid cyclobutylmethyl ester; MS: 517 (M+1)

[0361]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3,3,3-trifluoro-propyl ester; MS: 545 (M+1)

[0362]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-methoxy-ethyl ester; MS: 507 (M+1)

[0363]5,5-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 454 (M+1)

[0364]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-4,4-dimethyl-pentylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 493 (M+1)

[0365]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isopropoxy-ethyl ester; MS: 534 (M+1)

[0366]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3-methoxy-butyl ester; MS: 534 (M+1)

[0367]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isobutoxy-ethyl ester; MS: 549 (M+1)

[0368]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid 2-methoxy-ethyl ester; MS: 509 (M+1)

[0369]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 468 (M+1)

[0370]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 456 (M+1)

[0371]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 456 (M+1)

[0372]2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 458 (M+1)

[0373]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 468 (M+1)

[0374]2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 470 (M+1)

[0375]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-5-methyl-hexylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 479 (M+1)

[0376]2-[(N-Benzyl-morpholine-4-carboximidoyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide;MS: 495 (M+1).

[0377]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 438 (M+1).

[0378]{[1-(4-Cyano-1-methyl-piperdin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-pyrrolidin-1-yl-methyl}-carbamicacid ethyl ester; MS: 461 (M+1).

[0379]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-piperidin-1-yl-methyl}-carbamicacid ethyl ester; MS: 475 (M+1).

[0380]{Azepan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 489 (M+1).

[0381]{Azocan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 503 (M+1).

[0382]1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperidine-4-carboxylicacid ethyl ester; MS: 547 (M+1).

[0383]1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperidine-3-carboxylicacid ethyl ester; MS: 547 (M+1).

[0384][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 544 (M+1).

[0385]{[1,4′]Bipiperidinyl-1′-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}carbamicacid ethyl ester; MS: 558 (M+1).

[0386][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(4-phenyl-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 552 (M+1).

[0387][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(4-ethyl-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 504 (M+1).

[0388]{(4-Acetyl-piperazin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0389]4-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperazine-1-carboxylicacid ethyl ester; MS: 548 (M+1).

[0390][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(3,3,5-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methyl]-carbamicacid ethyl ester; MS: 543 (M+1).

[0391]{(3-Acetylamino-pyrrolidin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0392]{(3-Acetylamino-pyrrolidin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0393]{(3-Azapent-3-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 463 (M+1).

[0394]{(1-Methoxy-3-azapent-3-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 493 (M+1).

[0395][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(3-oxo-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 490 (M+1).

[0396]{(1,5-Dimethoxy-3-azapent-3-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 523 (M+1).

[0397]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0398]{(4-Carbamoyl-piperidin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1)

[0399][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2-methoxymethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 521 (M+1)

[0400](4-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperazin-1-yl)-aceticacid ethyl ester; MS: 562 (M+1)

[0401][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2,6-dimethyl-morpholin-4-yl)-methyl]carbamicacid ethyl ester; MS: 505 (M+1)

[0402][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2,6-dimethyl-morpholin-4-yl)-methyl]carbamicacid ethyl ester; MS: 505 (M+1)

[0403]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-thiomorpholin-4-yl)-methyl}-carbamicacid ethyl ester; MS: 493 (M+1)

[0404]4,4-Dimethyl-2-(6-methyl-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 454 (M+1)

[0405]2-(6-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 475 (M+1)

[0406]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 439 (M+1)

[0407]2-(7-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 475 (M+1)

[0408]5-Methyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0409]4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 453 (M+1)

[0410]3-tert-Butylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 472 (M+1)

[0411]{[2-tert-Butylsulfanyl-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 511 (M+1)

[0412]3-Benzylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 506 (M+1)

[0413]{[2-Benzylsulfanyl-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 545 (M+1)

[0414]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclooctyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 494 (M+1)

[0415]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cycloheptyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 480 (M+1)

[0416]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cycloheptyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 519 (M+1)

[0417]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclooctyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 533 (M+1)

[0418]{[1-(4-Cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid isobutyl ester; MS: 491 (M+1)

[0419]({1-[4-Cyano-1-(2-morpholin-4-yl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid isobutyl ester; MS: 604 (M+1)

[0420]({1-[1-2-Carbamoyl-ethyl)-4-cyano-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid isobutyl ester; MS: 562 (M+1)

[0421][(1-{4-Cyano-1-[2-(2-methoxyl-ethoxy)-ethyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 593 (M+1)

[0422][(1-{4-Cyano-1-[3-(2-methoxyl-ethoxy)-propyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 607 (M+1)

[0423]{[2-tert-Butoxy-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoly)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 495 (M+1)

[0424]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[diethyl-carbamoylimino)-morpholin-4-yl-methyl]-amino}-propionamide;MS: 504 (M+1)

[0425]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(3,3,5,5-tetramethyl-cyclohexyl)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 561 (M+1)

[0426]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(4,4-dipropyl-cyclohexyl)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 589 (M+1)

[0427]{[1-(4-Cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 505 (M+1)

[0428]{[1-(4-Cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 567 (M+1)

[0429]{[1-(4-Cyano-1-ethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 491 (M+1)

[0430]{[1-(-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 553 (M+1)

[0431]4-Cyano-4-{3-cyclohexyl-2-[(ethoxycarbonylimino-morpholin-4-yl-methyl)-amino]-propionylamino}-piperidine-1-carboxylicacid benzyl ester; MS: 597 (M+1)

[0432]{[-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 527 (M+1)

[0433]{[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 541 (M+1)

[0434] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-benzyl-4-cyano-piperidin-4-yl)-amide; MS: 488 (M+1)

[0435] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;MS: 508 (M+1)

[0436] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(4-fluoro-benzyl)-piperidin-4-yl]-amide; MS: 506 (M+1)

[0437] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-ethyl-piperidin-4-yl)-amide; MS: 426 (M+1)

[0438] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide; MS: 412 (M+1)

[0439] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-piperidin-4-yl)-amide; MS: 398 (M+1)

[0440] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-phenethyl-piperidin-4-yl)-amide; MS: 502 (M+1)

[0441] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(2,2-dimethyl-propyl)-piperidin-4-yl]-amide; MS: 468(M+1)

[0442] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3-dimethyl-butyl)-piperidin-4-yl]-amide; MS: 482(M+1)

[0443] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-pentyl-piperidin-4-yl)-amide; MS: 468 (M+1)

[0444] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-butyl-4-cyano-piperidin-4-yl)-amide; MS: 454(M+1)

[0445] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3,3-trifluoro-propyl)-piperidin-4-yl]-amide; MS: 494(M+1)

[0446] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl)-amide; MS: 494 (M+1)

[0447]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 494 (M+1)

[0448]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dipropyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 550 (M+1)

[0449]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4-tert-butyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 522 (M+1)

[0450]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 522 (M+1)

[0451]{[1-(3-Cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 477 (M+1).

[0452]2-[(Methanesulfonylimino-morpholin-4-yl-methyl)-amino]-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide. MS: 485 (M+1).

[0453]{[1-(3-Cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 465 (M+1).

[0454]({1-[3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester. MS: 533 (M+1).

[0455]{[1-(3-Cyano-1-ethyl-5,5-dimethyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 479 (M+1).

[0456] N-(4-Cyano-1-methyl-piperidin-4-yl)-3cyclohexyl-2-(7,8-difluoro-2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 474 (M+1)

[0457]{[1-(4-Cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 559 (M+1)

[0458]3-Cyano-3-[4,4-dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoylamino]-azepane-1-carboxylicacid benzyl ester; MS: 546 (M+1)

[0459] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (3-cyano-1-propyl-azepan-3-yl)-amide; MS: 454 (M+1)

[0460] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-azepan-4-yl)-amide; MS: 454 (M+1)

[0461]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid 4-methoxy-cyclohexylmethyl ester; MS: 575 (M+1)

[0462]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexyl ester; MS: 531 (M+1)

[0463]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 470 (M+1)

[0464]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 468 (M+1)

[0465]2-{[N-(4-Cyano-phenyl)-morpholine-4-carboximidoyl]-amino}-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 508 (M+1)

[0466]4,4-Dimethyl-2-{[N-(4-trifluoromethyl-phenyl)-morpholine-4-carboximidoyl]-amino}-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 551 (M+1)

[0467] The following are preferred compounds of the Formulas (Ia) and(Ib):

[0468] {[1-(3-cyano-1-isobutyl-piperdin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester, MS: 493 (M+1)

[0469]{[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 545 (M+1)

[0470]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexylmethyl ester; MS: 545 (M+1)

[0471]{[-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclobutyl ester; MS: 503 (M+1)

[0472]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid allyl ester; MS: 489 (M+1)

[0473]N-(4-Cyano-1-propyl-piperidin-4-yl)-4-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 480 (M+1)

[0474]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid tetrahydro-furan-3ylmethyl ester; MS: 533 (M+1)

[0475] {[-(4-cyano-1-methy-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamic acidtetrahydro-furan-2-ylmethyl ester; MS: 533 (M+1)

[0476]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6-difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;MS: 458 (M+1)

[0477]2-(5,6-Difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 460 (M+1)

[0478]2-(6-Fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 442 (M+1)

[0479]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(6-fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;MS: 440 (M+1)

[0480]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 465 (M+1)

[0481]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 463 (M+1)

[0482]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2,2-dimethyl-propyl ester; MS: 519 (M+1)

[0483]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 437 (M+1)

[0484]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid benzyl ester; MS: 539 (M+1)

[0485]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid isobutyl ester; MS: 505 (M+1)

[0486]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid propyl ester; MS: 491 (M+1)

[0487]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid hexyl ester; MS: 533 (M+1)

[0488]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid cyclobutylmethyl ester; MS: 517 (M+1)

[0489]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3,3,3-trifluoro-propyl ester; MS: 545 (M+1)

[0490]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-methoxy-ethyl ester; MS: 507 (M+1)

[0491]5,5-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 454 (M+1)

[0492]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isopropoxy-ethyl ester; MS: 534 (M+1)

[0493]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3-methoxy-butyl ester; MS: 534 (M+1)

[0494]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isobutoxy-ethyl ester; MS: 549 (M+1)

[0495]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid 2-methoxy-ethyl ester; MS: 509 (M+1)

[0496]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 468 (M+1)

[0497]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 456 (M+1)

[0498]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 456 (M+1)

[0499]2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 458 (M+1)

[0500]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 468 (M+1)

[0501]2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 470 (M+1)

[0502]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 438 (M+1).

[0503]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-pyrrolidin-1-yl-methyl}-carbamicacid ethyl ester; MS: 461 (M+1).

[0504]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-piperidin-1-yl-methyl}-carbamicacid ethyl ester; MS: 475 (M+1).

[0505]{Azepan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 489 (M+1).

[0506]{Azocan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 503 (M+1).

[0507]1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperidine-4-carboxylicacid ethyl ester; MS: 547 (M+1).

[0508]1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperidine-3-carboxylicacid ethyl ester; MS: 547 (M+1).

[0509][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(4-phenyl-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 552 (M+1).

[0510][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(4-ethyl-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 504 (M+1).

[0511]{(4-Acetyl-piperazin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0512]4-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperazine-1-carboxylicacid ethyl ester; MS: 548 (M+1).

[0513][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(3,3,5-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methyl]-carbamicacid ethyl ester; MS: 543 (M+1).

[0514]{(3-Acetylamino-pyrrolidin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0515]{(3-Acetylamino-pyrrolidin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0516]{(3-Azapent-3-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 463 (M+1).

[0517]{(1-Methoxy-3-azapent-3-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 493 (M+1).

[0518][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(3-oxo-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 490 (M+1).

[0519]{(1,5-Dimethoxy-3-azapent-3-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 523 (M+1).

[0520]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0521]{(4-Carbamoyl-piperidin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1)

[0522][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2-methoxymethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 521 (M+1)

[0523](4-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-ethoxycarbonylamino-methyl}-piperazin-1-yl)-aceticacid ethyl ester; MS: 562 (M+1)

[0524][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2,6-dimethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 505 (M+1)

[0525][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2,6-dimethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 505 (M+1)

[0526]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-thiomorpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 493 (M+1)

[0527]4,4-Dimethyl-2-(6-methyl-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 454 (M+1)

[0528]2-(6-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 475 (M+1)

[0529]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 439 (M+1)

[0530]2-(7-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 475 (M+1)

[0531]5-Methyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0532]4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 453 (M+1)

[0533]3-tert-Butylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 472 (M+1)

[0534]3-Benzylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 506 (M+1)

[0535]{[2-Benzylsulfanyl-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 545 (M+1)

[0536]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclooctyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 494 (M+1)

[0537]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cycloheptyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 480 (M+1)

[0538]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cycloheptyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 519 (M+1)

[0539]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclooctyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 533 (M+1)

[0540]{[1-(4-Cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid isobutyl ester; MS: 491 (M+1)

[0541]({1-[4-Cyano-1-(2-morpholin-4-yl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid isobutyl ester; MS: 604 (M+1)

[0542]({1-[1-2-Carbamoyl-ethyl)-4-cyano-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid isobutyl ester; MS: 562 (M+1)

[0543][(1-{4-Cyano-1-[2-(2-methoxyl-ethoxy)-ethyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 593 (M+1)

[0544][(1-{4-Cyano-1-[3-(2-methoxyl-ethoxy)-propyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 607 (M+1)

[0545]{[2-tert-Butoxy-1-(4-cyano-1-propyl-piperidin-4-ylcarbamoly)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 495 (M+1)

[0546]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[diethyl-carbamoylimino)-morpholin-4-yl-methyl]-amino}-propionamide;MS: 504 (M+1)

[0547]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(3,3,5,5-tetramethyl-cyclohexyl)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 561 (M+1)

[0548]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(4,4-dipropyl-cyclohexyl)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 589 (M+1)

[0549]{[1-(4-Cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 505 (M+1)

[0550]{[1-(4-Cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 567 (M+1)

[0551]{[1-(4-Cyano-1-ethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 491 (M+1)

[0552]{[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 553 (M+1)

[0553]4-Cyano-4-{3-cyclohexyl-2-[(ethoxycarbonylimino-morpholin-4-yl-methyl)-amino]-propionylamino}-piperidine-1-carboxylicacid benzyl ester; MS: 597 (M+1)

[0554]{[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 527 (M+1)

[0555]{[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 541 (M+1)

[0556] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-benzyl-4-cyano-piperidin-4-yl)-amide; MS: 488 (M+1)

[0557] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;MS: 508 (M+1)

[0558] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(4-fluoro-benzyl)-piperidin-4-yl]-amide; MS: 506 (M+1)

[0559] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-ethyl-piperidin-4-yl)-amide; MS: 426 (M+1)

[0560] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1methyl-piperidin-4-yl)-amide; MS: 412 (M+1)

[0561] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-piperidin-4-yl)-amide; MS: 398 (M+1)

[0562] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-phenethyl-piperidin-4-yl)-amide; MS: 502 (M+1)

[0563] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4cyano-1-(2,2-dimethyl-propyl)-piperidin-4-yl]-amide; MS: 468(M+1)

[0564] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3-dimethyl-butyl)-piperidin-4-yl]-amide; MS: 482(M+1)

[0565] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-pentyl-piperidin-4-yl)-amide; MS: 468 (M+1)

[0566] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-butyl-4-cyano-piperidin-4-yl)-amide; MS: 454(M+1)

[0567] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1(3,3,3-trifluoro-propyl)-piperidin-4-yl]-amide; MS: 494(M+1)

[0568] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl)-amide; MS: 494 (M+1)

[0569]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 494 (M+1)

[0570]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dipropyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 550 (M+1)

[0571]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4-tert-butyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 522 (M+1)

[0572]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(3,3,5,5-tetramethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 522 (M+1)

[0573]{[1-(3-Cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 477 (M+1).

[0574]{[1-(3-Cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 465 (M+1).

[0575]({1-[3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester. MS: 533 (M+1).

[0576]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(7,8-difluoro-2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 474 (M+1)

[0577]{[1-(4-Cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 559 (M+1)

[0578]3-Cyano-3-[4,4-dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoylamino]-azepane-1-carboxylicacid benzyl ester; MS: 546 (M+1)

[0579] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (3-cyano-1-propyl-azepan-3-yl)-amide; MS: 454 (M+1)

[0580] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-azepan-4-yl)-amide; MS: 454 (M+1)

[0581]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid 4-methoxy-cyclohexylmethyl ester; MS: 575 (M+1)

[0582]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexyl ester; MS: 531 (M+1)

[0583]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 470 (M+1)

[0584]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 468 (M+1)

[0585] More preferred compounds of the formulas (Ia) and (Ib) are chosenfrom the following:

[0586]{[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 545 (M+1)

[0587]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexylmethyl ester; MS: 545 (M+1)

[0588]{[-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclobutyl ester; MS: 503 (M+1)

[0589]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid allyl ester; MS: 489 (M+1)

[0590]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid tetrahydro-furan-3ylmethyl ester; MS: 533 (M+1)

[0591]{[1-(4-cyano-1-methy-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid tetrahydro-furan-2-ylmethyl ester; MS: 533 (M+1)

[0592]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 463 (M+1)

[0593]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2,2-dimethyl-propyl ester; MS: 519 (M+1)

[0594]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid benzyl ester; MS: 539 (M+1)

[0595]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid isobutyl ester; MS: 505 (M+1)

[0596]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid propyl ester; MS: 491 (M+1)

[0597]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid hexyl ester; MS: 533 (M+1)

[0598]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid cyclobutylmethyl ester; MS: 517 (M+1)

[0599]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3,3,3-trifluoro-propyl ester; MS: 545 (M+1)

[0600]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-methoxy-ethyl ester; MS: 507 (M+1)

[0601]5,5-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 454 (M+1)

[0602]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isopropoxy-ethyl ester; MS: 534 (M+1)

[0603]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3-methoxy-butyl ester; MS: 534 (M+1)

[0604]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isobutoxy-ethyl ester; MS: 549 (M+1)

[0605]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 456 (M+1)

[0606]2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 458 (M+1)

[0607]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 468 (M+1)

[0608]2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 470 (M+1)

[0609]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 438 (M+1).

[0610]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0611]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 439 (M+1)

[0612]2-(7-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 475 (M+1)

[0613]4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 453 (M+1)

[0614]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclooctyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 494 (M+1)

[0615]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cycloheptyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 480 (M+1)

[0616]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cycloheptyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 519 (M+1)

[0617]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclooctyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 533 (M+1)

[0618]({1-[1-2-Carbamoyl-ethyl)-4-cyano-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4yl-methylene)-carbamicacid isobutyl ester; MS: 562 (M+1)

[0619][(1-{4-Cyano-1-[2-(2-methoxyl-ethoxy)-ethyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 593 (M+1)

[0620][(1-{4-Cyano-1-[3-(2-methoxyl-ethoxy)-propyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 607 (M+1)

[0621]{[1-(4-Cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 505 (M+1)

[0622]{[1-(4-Cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 567 (M+1)

[0623]{[1-(4-Cyano-1-ethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 491 (M+1)

[0624]{[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 553 (M+1)

[0625] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-benzyl-4-cyano-piperidin-4-yl)-amide; MS: 488 (M+1)

[0626] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;MS: 508 (M+1)

[0627] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(4-fluoro-benzyl)-piperidin-4-yl]-amide; MS: 506 (M+1)

[0628] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-ethyl-piperidin-4-yl)-amide; MS: 426 (M+1)

[0629] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide; MS: 412 (M+1)

[0630] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-phenethyl-piperidin-4-yl)-amide; MS: 502 (M+1)

[0631] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(2,2-dimethyl-propyl)-piperidin-4-yl]-amide; MS: 468(M+1)

[0632] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3-dimethyl-butyl)-piperidin-4-yl]-amide; MS: 482(M+1)

[0633] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-pentyl-piperidin-4-yl)-amide; MS: 468 (M+1)

[0634] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-butyl-4-cyano-piperidin-4-yl)-amide; MS: 454(M+1)

[0635] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3,3-trifluoro-propyl)-piperidin-4-yl]-amide; MS: 494(M+1)

[0636] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl)-amide; MS: 494 (M+1)

[0637]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 494 (M+1)

[0638]{[1-(3-Cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 477 (M+1).

[0639]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(7,8-difluoro-2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 474 (M+1)

[0640]{[1-(4-Cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 559 (M+1)

[0641]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid 4-methoxy-cyclohexylmethyl ester; MS: 575 (M+1)

[0642]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexyl ester; MS: 531 (M+1)

[0643]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 470 (M+1)

[0644]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 468 (M+1)

[0645] Most preferred compounds of the formulas (Ia) and (Ib) are thosechosen from the following:

[0646] {[1-(3-cyano-1-isobutyl-piperdin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 493 (M+1)

[0647]{[1-(4-cyano-1-cyclohexyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 545 (M+1)

[0648]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexylmethyl ester; MS: 545 (M+1)

[0649]{[-1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclobutyl ester; MS: 503 (M+1)

[0650]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid allyl ester; MS: 489 (M+1)

[0651]N-(4-Cyano-1-propyl-piperidin-4-yl)-4-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 480 (M+1)

[0652]{[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid tetrahydro-furan-3ylmethyl ester; MS: 533 (M+1)

[0653]{[1-(4-cyano-1-methy-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid tetrahydro-furan-2-ylmethyl ester; MS: 533 (M+1)

[0654]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(6-fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;MS: 440 (M+1)

[0655]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid methyl ester; MS: 463 (M+1)

[0656]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2,2-dimethyl-propyl ester; MS: 519 (M+1)

[0657]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid benzyl ester; MS: 539 (M+1)

[0658]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid isobutyl ester; MS: 505 (M+1)

[0659]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid propyl ester; MS: 491 (M+1)

[0660]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid hexyl ester; MS: 533 (M+1)

[0661]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid cyclobutylmethyl ester; MS: 517 (M+1)

[0662]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3,3,3-trifluoro-propyl ester; MS: 545 (M+1)

[0663]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-methoxy-ethyl ester; MS: 507 (M+1)

[0664]5,5-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 454 (M+1)

[0665]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isopropoxy-ethyl ester; MS: 534 (M+1)

[0666]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 3-methoxy-butyl ester; MS: 534 (M+1)

[0667]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2-isobutoxy-ethyl ester; MS: 549 (M+1)

[0668]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 456 (M+1)

[0669]2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 458 (M+1)

[0670]N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;MS: 468 (M+1)

[0671]2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 470 (M+1)

[0672]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylidenemino)-propionamide;MS: 438 (M+1).

[0673]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-pyrrolidin-1-yl-methyl}-carbamicacid ethyl ester; MS: 461 (M+1).

[0674]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-piperidin-1-yl-methyl}-carbamicacid ethyl ester; MS: 475 (M+1).

[0675]{Azepan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 489 (M+1).

[0676]{Azocan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 503 (M+1).

[0677][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(4-phenyl-piperazin-1-yl)-methyl]-carbamicacid ethyl ester; MS: 552 (M+1).

[0678]{(4-Acetyl-piperazin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-methyl}-carbamicacid ethyl ester; MS: 518 (M+1).

[0679][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(3,3,5-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methyl]-carbamicacid ethyl ester; MS: 543 (M+1).

[0680]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0681][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2-methoxymethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 521 (M+1)

[0682][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2,6-dimethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 505 (M+1)

[0683][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-(2,6-dimethyl-morpholin-4-yl)-methyl]-carbamicacid ethyl ester; MS: 505 (M+1)

[0684]4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 439 (M+1)

[0685]2-(7-Chloro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 475 (M+1)

[0686]5-Methyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-hexanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 440 (M+1)

[0687]4,4Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide; MS: 453 (M+1)

[0688]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclooctyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 494 (M+1)

[0689]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cycloheptyl-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;MS: 480 (M+1)

[0690]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cycloheptyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 519 (M+1)

[0691]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclooctyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester; MS: 533 (M+1)

[0692]{[1-(4-Cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid isobutyl ester; MS: 491 (M+1)

[0693]({1-[4-Cyano-1-(2-morpholin-4-yl-ethyl)-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid isobutyl ester; MS: 604 (M+1)

[0694]({1-[1-2-Carbamoyl-ethyl)-4-cyano-piperidin-4-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid isobutyl ester; MS: 562 (M+1)

[0695][(1-{4-Cyano-1-[2-(2-methoxyl-ethoxy)-ethyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 593 (M+1)

[0696][(1-{4-Cyano-1-[3-(2-methoxyl-ethoxy)-propyl]-piperidin-4-ylcarbamoyl}-2-cyclohexyl-ethylamino)-morpholin-4-yl-methylene]-carbamicacid isobutyl ester; MS: 607 (M+1)

[0697]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(3,3,5,5-tetramethyl-cyclohexyl)-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 561 (M+1)

[0698]{[1-(4-Cyano-1-isopropyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 505 (M+1)

[0699]{[1-(4-Cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 567 (M+1)

[0700]{[1-(4-Cyano-1-ethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 491 (M+1)

[0701]{[1-(1-Benzyl-4-cyano-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 553 (M+1)

[0702]{[1-(4-cyano-1-phenethyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 541 (M+1)

[0703] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-benzyl-4-cyano-piperidin-4-yl)-amide; MS: 488 (M+1)

[0704] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;MS: 508 (M+1)

[0705] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(4-fluoro-benzyl)-piperidin-4-yl]-amide; MS: 506 (M+1)

[0706] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-ethyl-piperidin-4-yl)-amide; MS: 426 (M+1)

[0707] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-methyl-piperidin-4-yl)-amide; MS: 412 (M+1)

[0708] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-piperidin-4-yl)-amide; MS: 398 (M+1)

[0709] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-phenethyl-piperidin-4-yl)-amide; MS: 502 (M+1)

[0710] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(2,2-dimethyl-propyl)-piperidin-4-yl]-amide; MS: 468(M+1)

[0711] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3-dimethyl-butyl)-piperidin-4-yl]-amide; MS: 482(M+1)

[0712] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-pentyl-piperidin-4-yl)-amide; MS: 468 (M+1)

[0713] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (1-butyl-4-cyano-piperidin-4-yl)-amide; MS: 454(M+1)

[0714] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid [4-cyano-1-(3,3,3-trifluoro-propyl)-piperidin-4-yl]-amide; MS: 494(M+1)

[0715] 4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoicacid (4-cyano-1-cyclohexylmethyl-piperidin-4-yl)-amide; MS: 494 (M+1)

[0716]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 494 (M+1)

[0717]{[1-(3-Cyano-1-ethyl-pyrrolidin-3-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 477 (M+1).

[0718]{[1-(3-Cyano-1-propyl-pyrrolidin-3-ylcarbamoyl)-3,3-dimethyl-butylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester. MS: 465 (M+1).

[0719]({1-[3-Cyano-1-(4,4-dimethyl-cyclohexyl)-pyrrolidin-3-ylcarbamoyl]-3,3-dimethyl-butylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester. MS: 533 (M+1).

[0720]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(7,8-difluoro-2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide;MS: 474 (M+1)

[0721]{[1-(4-Cyano-1-cyclohexylmethyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid ethyl ester; MS: 559 (M+1)

[0722]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid 4-methoxy-cyclohexylmethyl ester; MS: 575 (M+1)

[0723]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylene}-carbamicacid cyclohexyl ester; MS: 531 (M+1)

[0724]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 470 (M+1)

[0725]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-phenyl-methylene}-carbamicacid ethyl ester; MS: 468 (M+1).

[0726] Any compounds of this invention containing one or more asymmetriccarbon atoms may occur as racemates and racemic mixtures, singleenantiomers, diastereomeric mixtures and individual diastereomers. Allsuch isomeric forms of these compounds are expressly included in thepresent invention. Each stereogenic carbon may be in the R or Sconfiguration unless otherwise specified, or a combination ofconfigurations.

[0727] Some of the compounds of formulas (Ia) and (Ib) can exist in morethan one tautomeric form. The invention includes all such tautomers.

[0728] It shall be understood by one of ordinary skill in the art thatall compounds of the invention are those which are chemically stable.

[0729] The invention includes pharmaceutically acceptable derivatives ofcompounds of formula (Ia) and (Ib). A “pharmaceutically acceptablederivative” refers to any pharmaceutically acceptable acid, salt orester of a compound of this invention, or any other compound which, uponadministration to a patient, is capable of providing (directly orindirectly) a compound of this invention, a pharmacologically activemetabolite or pharmacologically active residue thereof.

[0730] In addition, the compounds of this invention include prodrugs ofcompounds of the formulas (Ia) and (Ib). Prodrugs include thosecompounds that, upon simple transformation, are modified to produce thecompounds of the invention. Simple chemical transformations includehydrolysis, oxidation and reduction which occur enzymatically,metabolically or otherwise. Specifically, when a prodrug of thisinvention is administered to a patient, the prodrug may be transformedinto a compound of formula (Ia) and (Ib), thereby imparting the desiredpharmacological effect.

[0731] In order that the invention herein described may be more fullyunderstood, the following detailed description is set forth. As usedherein, the following abbreviations are used:

[0732] BOC or t-BOC is tertiary-butoxycarbonyl;

[0733] t-Bu is tertiary-butyl;

[0734] DMF is dimethylformamide;

[0735] EtOAc is ethyl acetate;

[0736] THF is tetrahydrofuran;

[0737] Ar is argon;

[0738] EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide hydrochlorideand

[0739] HOBT is 1-hydroxybenzotriazole.

[0740] Also, as used herein, each of the following terms, used alone orin conjunction with other terms, are defined as follows (except wherenoted to the contrary):

[0741] The term “alkyl” refers to a saturated aliphatic radicalcontaining from one to ten carbon atoms or a mono- or polyunsaturatedaliphatic hydrocarbon radical containing from two to twelve carbonatoms. The mono- or polyunsaturated aliphatic hydrocarbon radicalcontaining at least one double or triple bond, respectively. “Alkyl”refers to both branched and unbranched alkyl groups. Examples of “alkyl”include alkyl groups which are straight chain alkyl groups containingfrom one to eight carbon atoms and branched alkyl groups containing fromthree to eight carbon atoms. Other examples include lower alkyl groupswhich are straight chain alkyl groups containing from one to six carbonatoms and branched alkyl groups containing from three to six carbonatoms. It should be understood that any combination term using an “alk”or “alkyl” prefix refers to analogs according to the above definitionof“alkyl”. For example, terms such as “alkoxy”, “alkythio” refer toalkyl groups linked to a second group via an oxygen or sulfur atom.“Alkanoyl” refers to an alkyl group linked to a carbonyl group (C═O).Each alkyl or alkyl analog described herein shall be understood to beoptionally partially or fully halogenated.

[0742] The term “cycloalkyl” refers to the cyclic analog of an alkylgroup, as defined above. Examples of cycloalkyl groups are saturated orunsaturated nonaromatic cycloalkyl groups containing from three to eightcarbon atoms, and other examples include cycloalkyl groups having threeto six carbon atoms. Each cycloalkyl described herein shall beunderstood to be optionally partially or fully halogenated.

[0743] The term “aryl” refers to phenyl and naphthyl.

[0744] The term “halo” refers to a halogen radical selected from fluoro,chloro, bromo or iodo. Representative halo groups of the invention arefluoro, chloro and bromo.

[0745] The term “heteroaryl” refers to a stable 5-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicaromatic heterocycle radical. Each heterocycle consists of carbon atomsand from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. Theheterocycle may be attached by any atom of the cycle, which results inthe creation of a stable structure. Examples of “heteroaryl” includeradicals such as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl,imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl, benzothienyl,indazolyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, purinyl,quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, pteridinyl, carbazolyl,acridinyl, phenazinyl, phenothiazinyl and phenoxazinyl,

[0746] The term “heterocycle” refers to a stable 4-8 membered (butpreferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated, and isnon-aromatic. Each heterocycle consists of carbon atoms and from 1 to 4heteroatoms chosen from nitrogen, oxygen and sulfur. The heterocycle maybe attached by any atom of the cycle, which results in the creation of astable structure. Examples of “heterocycle” include radicals such aspyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl,indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl,1,4,5,6-tetrahydropyrimidin-2-ylamine, dihydro-oxazolyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione.

[0747] The terms “heterocycle”, “heteroaryl” or “aryl”, when associatedwith another moiety, unless otherwise specified shall have the samemeaning as given above. For example, “aroyl” refers to phenyl ornaphthyl linked to a carbonyl group (C═O).

[0748] Each aryl or heteroaryl unless otherwise specified includes it'spartially or fully hydrogenated derivative. For example, quinolinyl mayinclude decahydroquinolinyl and tetrahydroquinolinyl, naphthyl mayinclude it's hydrogenated derivatives such as tetrahydranaphthyl. Otherpartially or fully hydrogenated derivatives of the aryl and heteroarylcompounds described herein will be apparent to one of ordinary skill inthe art.

[0749] The term heterocycle as it pertains to “Het” shall to beunderstood to mean a stable non-aromatic spiroheterocycle, 4-8 membered(but preferably, 5 or 6 membered) monocyclic, 8-11 membered bicyclicheterocycle radical which may be either saturated or unsaturated or aC6-C10 bridged bicyclo wherein one or more carbon atoms are optionallyreplaced by a heteroatom. Each heterocycle consists of carbon atoms andfrom 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur. Theheterocycle may be attached by any atom of the cycle, which results inthe creation of a stable structure. Examples of “Het” include thefollowing heterocycles: azepanyl, piperidinyl, pyrrolidinyl, azetidinyl,oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl,oxetanyl, azocanyl, oxocanyl, 1,3-diazocanyl, 1,4-diazocanyl,1,5-diazocanyl, 1,3-dioxocanyl, 1,4-dioxocanyl, 1,5-dioxocanyl,1,3-oxazocanyl, 1,4-oxazocanyl, 1,5-oxazocanyl, 1,3-diazepanyl,1,4-diazepanyl, 1,3-dioxepanyl, 1,4-dioxepanyl, 1,3-oxazepanyl,1,4-oxazepanyl, 1,2-thiazocanyl-1,1-dioxide,1,2,8-thiadiazocanyl-1,1-dioxide, 1,2-thiazepanyl-1,1-dioxide,1,2,7-thiadiazepanyl-1,1-dioxide, tetrahydrothiophenyl,hexahydropyrimidinyl, hexahydropyridazinyl, piperazinyl,1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl, dihydro-oxazolyl,dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl, oxazolidinyl,1,2-thiazinanyl-1,1-dioxide, 1,2,6-thiadiazinanyl-1,1-dioxide,isothiazolidinyl-1,1-dioxide, imidazolidinyl-2,4-dione, imidazolidinyl,morpholinyl, dioxanyl, tetrahydropyridinyl, thiomorpholinyl,thiazolidinyl, dihydropyranyl, dithianyl, decahydro-quinolinyl,decahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, indolinyl,octahydro-quinolizinyl, dihydro-indolizinyl, octahydro-indolizinyl,octahydro-indolyl, decahydroquinazolinyl, decahydroquinoxalinyl,1,2,3,4-tetrahydroquinazolinyl or 1,2,3,4-tetrahydroquinoxalinyl,aza-bicyclo[3.2.1]octane, aza-bicyclo[2.2.1]heptane,aza-bicyclo[2.2.2]octane, aza-bicyclo[3.2.2]nonane,aza-bicyclo[2.1.1]hexane, aza-bicyclo[3.1.1]heptane,aza-bicyclo[3.3.2]decane and 2-oxa or2-thia-5-aza-bicyclo[2.2.1]heptaneeach; heterocyclic ring beingsubstituted with one or more R₅. The substituent R₅ is defined above.

[0750] As used herein above and throughout this application, “nitrogen”and “sulfur” include any oxidized form of nitrogen and sulfur and thequaternized form of any basic nitrogen.

[0751] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating preferred embodiments of this invention, and are not to beconstrued as limiting the scope of the invention in any way.

[0752] The examples which follow are illustrative and, as recognized byone skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds. Starting materials used inthe scheme below are either commercially available or easily preparedfrom commercially available materials by those skilled in the art.

GENERAL SYNTHETIC METHODS

[0753] The invention also provides processes of making the present novelcompounds of formula (Ia) and (Ib). Compounds of the invention may beprepared by methods described below, those found in U.S. applicationSer. No. 09/655,351, incorporated herein be reference in it's entirety,and by methods known to those of ordinary skill in the art.

[0754] A key intermediate in the preparation of compounds of formula(Ia) and (Ib) is the dipeptide nitrile intermediate (III).

[0755] The synthesis of intermediates of formula (III) is described inU.S. provisional patent application 60/222,900 and outlined below inSchemes I and II.

[0756] As illustrated in Scheme I, an amino acid bearing a suitableprotecting group R′ (IV), is reacted with an amino nitrile (V) undersuitable coupling conditions. An example of a suitable protecting groupis the t-butoxycarbonyl (BOC) group. An example of standard couplingconditions would be combining the starting materials in the presence ofa coupling reagent such as 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide(EDC) with 1-hydroxybenzotriazole (HOBT), in a suitable solvent such asDMF or methylene chloride. A base such as N-methylmorpholine may beadded. This is followed by deprotection to give amino acid nitrile III.

[0757] The intermediate aminonitrile (V) used in Scheme I above may beprepared as outlined in Scheme II.

[0758] In this method, a ketone bearing “Het” (VII) is reacted with an aprimary amine or an ammonium salt, such as ammonium chloride, and acyanide salt, such as potassium cyanide or sodium cyanide, in a suitablesolvent, such as water or a solution of ammonia in methanol, at aboutroom temperature to reflux temperature.

[0759] Compounds having formula (Ia/Ib) may be prepared by Methods A-D,as illustrated in Schemes III-VI.

[0760] According to Method A, a dipeptide nitrile intermediate (III), ora basic salt thereof, is allowed to react with (VIII) in the presence ofa suitable coupling agent to provide the desired product (Ia/Ib).Suitable reaction conditions are known to those skilled in the art andsome examples of suitable coupling agents include2-chloro-1-methylpyridinium iodide (Yong, Y. F. et al., J. Org. Chem.1997, 62, 1540), phosgene or triphosgene (Barton, D. H. et al., J. Chem.Soc. Perkin Trans. I, 1982, 2085), alkyl halides (Brand, E. and Brand,F. C., Org. Synth., 1955, 3, 440) carbodiimides (Poss, M. A. et al.,Tetrahedron Lett., 1992, 40, 5933) and mercury salts (Su, W., SyntheticComm., 1996, 26, 407 and Wiggall, K. J. and Richardson, S. K. J.,Heterocyclic Chem., 1995, 32, 867).

[0761] Compounds having formulas (Ia) and (Ib) may also be prepared byMethod B as illustrated in Scheme IV, where R is an alkyl or aryl group.

[0762] According to Method B a dipeptide nitrile intermediate (III), ora basic salt thereof, is allowed to react with IX, with or without anadded base such as triethylamine, to provide the desired product(Ia/Ib). Suitable reaction conditions are known to those skilled in theart and examples of such amine additions may be found in the chemicalliterature, for example Haake, M. and Schummelfeder, B., Synthesis,1991, 9, 753; Dauwe, C. and Buddrus, J., Synthesis 1995, 2, 171; Ried,W. and Piechaczek, D., Justus Liebigs Ann. Chem. 1966, 97, 696 and Dean,W. D. and Papadopoulos, E. P., J. Heterocyclic Chem., 1982, 19, 1117.

[0763] The intermediate IX is either commercially available or can besynthesized by methods known to those skilled in the art and describedin the literature, for example Francesconi, I. et. al., J. Med. Chem.1999, 42, 2260; Kurzer, F., Lawson, A.,Org. Synth. 1963, 645, andGutman, A. D. U.S. Pat. No. 3,984,410, 1976.

[0764] In a similar reaction, intermediate X having a halogen or othersuitable leaving group (X′) may be used in place of intermediate IX, asillustrated in Method C, Scheme V.

[0765] According to Method C, a dipeptide nitrile intermediate, or abasic salt thereof, is allowed to react with intermediate X, with orwithout an added base such as triethylamine, to provide the desiredproduct (Ia/Ib). Procedures for accomplishing this reaction are known tothose skilled in the art and described in the chemical literature (forexample, Dunn, A. D., Org. Prep. Proceed. Int., 1998, 30, 709;Lindstroem, S. et al., Heterocycles, 1994, 38, 529; Katritzky, A. R. andSaczewski, F., Synthesis, 1990, 561; Hontz, A. C. and Wagner, E. C., OrgSynth., 1963, IV, 383; Stephen, E. and Stephen, H., J. Chem. Soc., 1957,490).

[0766] Compounds having formula (Ia/Ib) in which R₁ is an amine may alsobe prepared by Method D as illustrated in Scheme VI.

[0767] According to Method D, a carbodiimide (XI) derivative of (III) isallowed to react with an amine (R₁) to provide the desired guanidine(Ia/Ib) product. The conversion of amines to carbodiimides is known tothose in the art and described in the literature (for example, Pri-Bar,I. and Schwartz, J., J. Chem. Soc. Chem. Commun., 1997, 347; Hirao, T.and Saegusa, T., J. Org. Chem., 1975, 40, 298). The reaction ofcarbodiimides with amine nucleophiles is also described in theliterature (for example, Yoshiizumi, K. et al., Chem. Pharm. Bull.,1997, 45, 2005; Thomas, E. W. et al., J. Med. Chem., 1989, 32, 228;Lawson, A. and Tinkler, R. B., J. Chem. Soc. C, 1971, 1429.

[0768] In a modification of Method D, one may start with the thioureaXII (formed by reaction of the corresponding amine with anisothiocyanate R₆N═C═S) and then form the corresponding carbodiimide(XI) in situ by reaction with a suitable desulfurizing agent, such asHgCl₂, in a suitable solvent such as DMF or acetonitrile.

[0769] Compounds of formula (Ib), where R₁ is an amine may be preparedusing a general procedure described by M. Haake and B. Schummfelder(Synthesis, 1991, 753). According to this procedure (Method E, SchemeVII), intermediate XIII bearing two suitable leaving groups Z, such asphenoxy groups, is reacted sequentially with amines R₁ and R₆R₈NH in asuitable solvent such as methanol or isopropanol to provide the desiredproduct. Reaction of the first amine may be carried out at about roomtemperature and reaction of the second amine is preferentially carriedout with heating at the reflux temperature of the solvent. If XIII isallowed to react with a bifunctional nucleophile intermediate XIV, whereY is a nucleophilic heteroatom such as N, O or S, one may obtain theproduct of formula (Ib) where R₁ and R₆ form a heterocyclic ring.Intermediate XIII may be prepared by reaction of III (R₄=H) withdichlorodiphenoxymethane, which in turn, may be prepared by heatingdiphenyl carbonate with PCl₅ (R. L. Webb and C. S. Labow, J. Het. Chem.,1982, 1205).

[0770] In order that this invention be more fully understood, thefollowing examples are set forth. These examples are for the purpose ofillustrating embodiments of this invention, and are not to be construedas limiting the scope of the invention in any way.

[0771] The examples which follow are illustrative and, as recognized byone skilled in the art, particular reagents or conditions could bemodified as needed for individual compounds without undueexperimentation. Starting materials used in the scheme below are eithercommercially available or easily prepared from commercially availablematerials by those skilled in the art.

SYNTHETIC EXAMPLES Example 1

[0772]

[0773]2-{[Acetylimino-(4-methoxy-phenyl)-methyl]-amino}-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide(Method A).

[0774] (a) N-(4-methoxy-thiobenzoyl)acetamide.

[0775] A solution of acetyl chloride (4.69 g, 59.8 mmol) in acetone (20mL) was added dropwise to a solution of 4-methoxythiobenzamide (5.00 g,29.9 mmol) and pyridine (4.76 g, 60.1 mmol) in acetone (30 mL). Thereaction mixture was heated to reflux for 30 min then poured onto icewater. The resulting precipitate was isolated via filtration and driedunder vacuum overnight to provide a light yellow/orange solid (4.52 g,72%). ¹H NMR (400 MHz, CDCl₃) δ 2.56 (s, 3H), 3.87 (s, 3H), 6.89 (dd,J=6.9, 2.0 Hz, 2H), 7.77 (dd, J=6.9, 2.0 Hz, 2H).

[0776] (b)2-{[Acetylimino-(4-methoxy-phenyl)-methyl]-amino}-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide.

[0777] 2-Chloro-N-methylpyridinium iodide (660 mg, 2.58 mmol), was addedto a solution of N-(4-methoxy-thiobenzoyl)acetamide (420 mg, 2.01 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (730 mg, 2.00 mmol), andN,N-diisopropylethylamine (1.05 mL, 6.02 mmol) in dichloromethane (8.0mL). The reaction mixture was stirred at room temperature for 2 h, thendiluted with dichloromethane (100 mL)and washed with 2×150 mL ofsaturated sodium bicarbonate. The organic phase was dried (MgSO₄) andconcentrated. The resulting residue was chromatographed over 100 g offlash silica first using EtOAc, then dichloromethane/methanol 9:1 as theeluant to provide the desired product as an off white solid (377 mg,40%). ¹H NMR (400 MHz, DMSO-d6) δ 0.70-0.90 (m, 2H), 1.00-1.30 (m, 4H),1.35-1.65 (m, 8H), 1.72 (s, 3H), 1.85-2.20 (m, 6H), 2.48-2.60 (m, 1H),3.78 (s, 3H), 4.20-4.35 (m, 1H), 6.95-6.99 (m, 2 H), 7.33 (d, J=8.4 Hz,1H), 7.72 (d, J=8.4 Hz, 1H). MS, m/z 468=M+1.

Example 2

[0778]

[0779]2-[(Acetylimino-phenyl-methyl)-amino]-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide.

[0780] (a) Thiobenzoyl acetamide was prepared according to the procedurefrom Example 1, step a, starting with thiobenzamide.

[0781] (b) The title compound was prepared starting from thiobenzoylacetamide and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 1, stepb. MS, m/z 438=M+1.

Example 3

[0782]

[0783]2-{[Acetylimino-(4-fluoro-phenyl)-methyl]-amino}-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide.

[0784] (a) N-(4-Fluoro-thiobenzoyl)acetamide was prepared according tothe procedure from Example 1, step a, starting with4-fluorothiobenzamide.

[0785] (b) The title compound was prepared starting fromN-(4-fluoro-thiobenzoyl) acetamide and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 1, stepb. MS, m/z 456=M+1.

Example 4

[0786]

[0787]2-[(Acetylimino-phenyl-methyl)]-amino]-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamide.

[0788] (a) The title compound was prepared starting from thiobenzoylacetamide and2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 1, stepb, except that the compound was purified by HPLC using a 20×250 mm C18reverse phase column with the method being 20% acetonitrile in water to90% acetonitrile in water. MS, m/z 480=M+1.

Example 5

[0789]

[0790]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylen}-carbamicacid ethyl ester (Method A).

[0791] (a) (Morpholine-4-carbothioyl)-carbamic acid ethyl ester.

[0792] Morpholine (7.5 mL, 86.0 mmol) was added dropwise to a solutionof ethyl isothiocyanato formate (10.0 mL, 84.8 mmol) in tetrahydrofuran(200 mL). The reaction mixture was stirred at room temperature for 2.5h, then concentrated and dried under vacuum to provide the desiredproduct as a white solid (16.5 g, 89%). This material was used withoutfurther purification. ¹H NMR (400 MHz, CDCl₃) δ 1.28 (t, J=7.1 Hz, 3H),3.61-3.97 (m, 8H), 4.16 (q, 7.1 Hz, 2H), 7.44 (br s, 1H).

[0793] (a){[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-morpholin-4-yl-methylen}-carbamicacid ethyl ester.

[0794] 2-Chloro-N-methylpyridinium iodide (680 mg, 2.66 mmol), was addedto a solution of (morpholine-4-carbothioyl)-carbamic acid ethyl ester(450 mg, 2.06 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (745 mg, 2.04 mmol), andN,N-diisopropylethylamine (1.10 mL, 6.3 mmol) in dichloromethane (8.0mL). The reaction was stirred at room temperature for 2.5 h then takenup in 10% citric acid solution and washed with EtOAc. The aqueous phasewas then basified with saturated sodium carbonate and extracted withEtOAc. The organic extract was dried (MgSO₄) and concentrated to providethe desired product as a white solid (250 mg, 26%). This material wasfurther purified by HPLC using a 20×250 mm C₁₈ reverse phase column withthe method being 20% acetonitrile in water to 90% acetonitrile in water.MS, m/z 477=M+1.

Example 6

[0795]

[0796]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester.

[0797] The title compound was prepared starting from(morpholine-4-carbothioyl)-carbamic acid ethyl ester and2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt according to the procedure from Example 5, stepb, except that the compound was first purified by chromatography oversilica gel using 9:1 methylene chloride:methanol as the eluant prior toreverse phase HPLC purification. MS, m/z 505=M+1.

Example 7

[0798]

[0799]{[1-(4-Cyano-1-propyl-piperidin-4-ylcarbamoyl)-3,3-dimethyl-butylimino]-morpholin-4-yl-methyl}-carbamicacid ethyl ester.

[0800] The title compound was prepared starting from(morpholine-4-carbothioyl)-carbamic acid ethyl ester and2-amino-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt accordingto the procedure from Example 5. MS, m/z 460=M+1.

Example 8

[0801]

[0802]({1-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-ylcarbamoyl]-2-cyclohexyl-ethylamino}-morpholin-4-yl-methylene)-carbamicacid ethyl ester.

[0803] The title compound was prepared starting from(morpholine-4-carbothioyl)-carbamic acid ethyl ester and2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 5, stepb,. MS, m/z 519=M+1.

Example 9

[0804]

[0805]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide(Method B).

[0806] (a) Benzimidic Acid Methyl Ester.

[0807] Benzimidic acid methyl ester hydrochloride (5 g, 29.1 mmol) waspartitioned between saturated sodium carbonate solution (200 mL) anddiethyl ether (100 mL). The organic layer was dried (MgSO₄) andconcentrated to provide the desired product as a colorless liquid (3.20g, 81%). This material was used without further purification. ¹H NMR(400 MHz, CDCl₃) δ 3.93 (s, 3H), 7.39-7.46 (m, 3H), 7.75 (d, J=1.1 Hz,2H).

[0808] (a) 1-Ethyl-3-(methoxy-phenyl-methylene)-urea.

[0809] A neat mixture of benzimidic acid methyl ester (750 mg, 5.56mmol) and ethyl isocyanate (808 mg, 11.3 mmol) was stirred at 50° C. for24 h. Excess isocyanate was removed under vacuum to provide the desiredproduct as a colorless viscous oil (1.09 g, 95%). This material was usedwithout further purification. ¹H NMR (400 MHz, CDCl₃) δ 1.07 (t, J=7.3Hz, 3 H), 3.25 (q, J=7.3 Hz, 2 H), 3;87 (s, 3H), 4.97 (br s, 1H),7.26-7.40 (m, 2H), 7.45 (d, J=7.4 Hz, 1H), 7.69-7.71 (m, 2H). MS, m/z207=M+1.

[0810] (a)N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-[(ethylcarbamoylimino-phenyl-methyl)-amino]-propionamide.

[0811] A solution of 1-ethyl-3-(methoxy-phenyl-methylene)-urea (350 mg,1.70 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (512 mg, 1.40 mmol) and N,N-diisopropylethylamine(352 mg, 2.73 mmol) in dry methanol (5.0 mL) was stirred at roomtemperature for 60 h. The reaction mixture was concentrated and theresulting residue was chromatographed over 50 g of flash silica gelusing dichloromethane to 5% methanol in dichloromethane as the eluant.This provided the desired product as a light yellow solid (280 mg, 43%)which was further purified by HPLC using a 20×250 mm C₁₈ reverse phasecolumn with the method being 20% acetonitrile in water to 90%acetonitrile in water. MS, m/z 467=M+1.

Example 10

[0812]

[0813]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide(Method C).

[0814] A suspension of 3-chloro-benzo[d]isothiazole 1,1-dioxide (300 mg,1.49 mmol) and2-amino-N-(-4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt (500 mg, 1.37 mmol) was prepared in 5.5 mL ofacetonitrile. Triethylamine (575 μL, 4.10 mmol) was added and thereaction mixture was stirred at room temperature for 1 day. Thesuspension was filtered to remove triethylamine hydrochloride and thefiltrate was concentrated. The resulting residue was chromatographedover 50 g of flash silica using dichloromethane/methanol 9:1 as theeluant to provide the desired product as a light yellow solid (310 mg,49%). ¹H NMR (400 MHz, CDCl₃) δ 0.25-0.45 (m, 1H), 0.65-0.85 (m, 2H),0.95-1.10 (m, 2H), 1.30-1.60 (m, 7H), 1.75-1.85 (m, 2H), 1.85-2.2 (m,2H), 2.31 (s, 3H), 2.35-2.50 (m, 3H), 2.65-2.80 (m, 2H), 4.60-4.70 (m,1H), 7.35-7.50 (m, 2H), 7.58 (t, J=7.3, 1H), 7.78 (d, J=7.7 Hz, 1H),7.81 (br s, 1H), 8.91 (br s, 1H). MS, m/z 458=M+1.

Example 11

[0815]

[0816]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide.

[0817] The title compound was prepared starting from3-chloro-benzo[d]isothiazole 1,1-dioxide and2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt according to the procedure from Example 10,except that the compound was further purified by HPLC using a 20×250 mmC₁₈ reverse phase column with the method being 20% acetonitrile in waterto acetonitrile. MS, m/z 486=M+1.

Example 12

[0818]

[0819]2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-4,4-dimethyl-pentanoicacid(4-cyano-1-propylpiperidin-4-yl)-amide.

[0820] The title compound was prepared starting from3-chloro-benzo[d]isothiazole 1,1-dioxide and2-amino-4,4-dimethyl-pentanoic acid(4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride salt accordingto the procedure from Example 10, except that the compound was furtherpurified by HPLC using a 20×250 mm C₁₈ reverse phase column with themethod being 20% acetonitrile in water to acetonitrile. MS, m/z 460=M+1.

Example 13

[0821]

[0822]N-[3-Cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide.

[0823] The title compound was prepared starting from 3-chlorobenzo[d]isothiazole 1,1-dioxide and2-amino-N-[3-cyano-1-(1-ethyl-propyl)-pyrrolidin-3-yl]-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 10,except that the compound was further purified by HPLC using a 20×250 mmC₁₈ reverse phase column with the method being 40% acetonitrile in waterto acetonitrile. MS, m/z 500=M+1.

Example 14

[0824]

[0825]N-(3-Cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ⁶-benzo[d]isothiazol-3-ylamino)-propionamide.

[0826] The title compound was prepared starting from 3-chlorobenzo[d]isothiazole 1,1-dioxide and2-amino-N-(3-cyano-1-cyclohexyl-pyrrolidin-3-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 10,except that the compound was further purified by HPLC using a 20×250 mmC₁₈ reverse phase column with the method being 40% acetonitrile in waterto acetonitrile. MS, m/z 512=M+1.

Example 15

[0827]N-(4-Cyano-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-oxo-3H-isoindol-1-ylamino)-propionamide.

[0828] The title compound was prepared starting from3-imino-2,3-dihydro-isoindol-1-one and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 10,except that refluxing THF was used as the solvent. The compound wasfurther purified by HPLC using a 20×250 mm C₁₈ reverse phase column withthe method being 20% acetonitrile in water to acetonitrile. MS, m/z422.5=M+1.

Example 16

[0829]

[0830]4,4-Dimethyl-2-(3-oxo-3H-isoindol-1-ylamino)-pentanoicacid-(4-cyano-1-propyl-piperidin-4-yl)-amide.

[0831] The title compound was prepared from3-imino-2,3-dihydro-isoindol-1-one and 2-amino-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)amide bis hydrochloride saltaccording to the procedure from Example 15. MS, m/z 424.5=M+1.

Example 17

[0832]

[0833]N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6-difluoro-3-oxo-3H-isoindol-1-ylamino)propionamide.

[0834] (a) 2-Chloro-4,5-difluorobenzoic acid methyl ester.

[0835] 2-Chloro-4,5-difluorobenzoic acid (1.93 g, 10 mmol) was dissolvedin 20 mL of acetone. Cesium carbonate (5.29 g, 15 mmol) was addedfollowed by iodomethane (1.0 mL, 15 mmol). This reaction mixture washeated under reflux for 1 h and then cooled to room temperature. Thissuspension was then diluted with 40 mL of ethyl ether. The solid wasremoved by filtration and washed with ethyl ether. The filtrate wasevaporated in vacuo to give the title compound in quantitative yield asa clear oil.

[0836] (b) 2-Cyano-4,5-difluorobenzoic acid methyl ester.

[0837] The above oil (2.06 g, 10 mmol) was dissolved in 10 mL ofN-methyl pyrrolidinone. Copper (I) cyanide (1.79 g, 20 mmol) was added.This mixture was heated at 195° C. under nitrogen for 1 h. After coolingto room temperature, this solution was diluted with 100 mL of water. Theresulting solid was collected by filtration. This solid was thensuspended in a rapidly stirred solution of potassium cyanide (0.5 g) in30 mL of water for 1 h. EtOAc (30 mL) was added. The mixture wasfiltered through diatomaceous earth. The organic phase was separated andthe aqueous phase was extracted with EtOAc (20 mL×2). The combinedorganic phase was washed with brine and dried over magnesium sulfate.The solvent was removed in vacuo. The residue was crystallized fromethyl ether and petroleum ether to give the title compound as a yellowsolid (1.26 g, 64%).

[0838] (c) 5,6-Difluoro-2,3-dihydro-3-imino-1H-isoindol-1-one.

[0839] The above solid (0.493 g, 2.5 mmol) was dissolved in 20 mL ofMeOH. This solution was saturated with ammonia at 0° C. and then stirredin a pressure tube at room temperature for 3 days. The solid wascollected by filtration and washed with ethyl ether to give the titlecompound as a yellow solid (0.363 g, 80%).

[0840] The title compound was prepared from5,6-difluoro-2,3-dihydro-3-imino-1H-isoindol-1-one and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 15. MS,m/z 458.3=M+1.

Example 18

[0841]

[0842]N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide.

[0843] The title compound was prepared starting from4-chloro-benzo[e][1,3]oxazin-2-one (prepared from benzo[e][1,3]oxazin-2,4-dione and PCl₅ in refluxing toluene) and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt according to the procedure from Example 10. MS,m/z 438=M+1.

Example 19

[0844]

[0845]N-(4-cyano-1-methyl-piperidin-4-yl)-2-(4-cyano-pyrimidin-2-ylamino)-3-cyclohexyl-propionamide(Method C).

[0846] 2-Chloro-4-pyrimidinecarbonitrile (0.3 mmol, Daves, G. D. Jr.,O'Brien, D. E., Cheng, C. C. J. Het. Chem, 1964, 1, 130) and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamide(0.7 mmol) were dissolved in acetonitrile (10 mL) containingN,N-diisopropylethylamine (0.6 mmol). The solution was heated to agentle reflux for 17 h. The volatiles were evaporated and the residuewas subjected to chromatography (silica gel, eluant=EtOAc then MeOH).The methanolic fraction was concentrated to a colorless solid which wasrechromatographed (10% MeOH/EtOAc) to afford the title compound as acolorless solid (52%). The material was recrystallized fromdichloromethane/petroleum ether.

Example 20

[0847]

[0848]N-(4-cyano-1-methyl-piperidin-4-yl)-2-(4-trifluoromethyl-pyrimidin-2-ylamino)-3-cyclohexyl-propionamide.

[0849] The title compound was prepared from 2-chloro-4-trifluoromethylpyrimidine and2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamideaccording to the procedure from Example 19. MS, m/z 439.5=M+1.

Example 21

[0850]

[0851]N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-2[N-cyano-morpholine-4-carboximidoyl)-amino]-propionamide(Method D).

[0852] (a)2-(N-Cyano-iminomethylene-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide.

[0853] A solution of diphenylcyanocarbonimidate (455 mg, 1.91 mmol),2-amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidebis hydrochloride salt (680 mg, 1.86 mmol) and N,N-diisopropylethylamine(482 mg, 3.73 mmol) in isopropanol (5.0 mL) was stirred overnight atroom temperature. The reaction mixture was then filtered to provide thedesired carbodiimide as a white powder (140 mg, 22%). This material wasused without further purification. ¹H NMR (400 MHz, CDCl₃) δ 0.80-1.00(m, 2H), 1.05-1.20 (m, 1H), 1.20-1.40 (2H), 1.50-1.85 (m, 8H), 2.32 (s,3H), 2.40-2.50 (m, 2H), 2.55-2.70 (m, 4H), 2.85-2.95 (m, 2H), 4.10-4.20(m, 1H), 8.77 (br s, 1H). MS, m/z 343=M+1.

[0854] (b)2-(N-Cyano-benzimidoyl-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide.

[0855] A suspension of2-(N-cyano-iminomethylene-amino)-N-(4-cyano-1-methyl-piperidine-4-yl)-3-cyclohexyl-propionamide(120 mg, 0.35 mmol) in tetrahydrofuran (1 mL) was treated withmorpholine (4 mL, 45.9 mmol). The reaction mixture was stirred at roomtemperature for 3 days then concentrated to dryness. The residue waspurified by HPLC using a 20×250 mm C₁₈ reverse phase column with themethod being 20% acetonitrile in water to 90% acetonitrile in water. MS,m/z 430=M+1.

Example 22

[0856]

[0857]N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-{[(diethyl-carbamoylimino)-morpholin-4-yl-methyl]-amino}-propionamide(Method D).

[0858] (a) N,N-Diethyl carbamoyl thiocyanate.

[0859] A suspension of sodium thiocyanate (3.30 g, 40.7 mmol) in dryacetonitrile (25 mL) at 80° C. was treated dropwise with a solution ofN,N-diethyl carbamoyl chloride (5.0 g, 36.9 mmol) in dry acetonitrile(15 mL). The reaction mixture was stirred at 80° C. for 50 min, cooledto room temperature, then filtered through a fine glass frit. Theresulting filtrate was used as a 0.9 M solution of N,N-diethyl carbamoylthiocyanate in acetonitrile.

[0860] (b)N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(3-diethylamino-carbonyl-thioureido)-propionamide

[0861] A solution of2-amino-N-(-4-cyano-1-propyl-piperidin-4-yl)-3-cyclohexylpropionamidebis hydrochloride salt (560 mg, 1.53 mmol) and triethylamine (500 μL,3.59 mmol) in acetonitrile (4 mL) was treated with a solution ofN,N-diethyl carbamoyl thiocyanate in acetonitrile (3.0 mL, 2.7 mmol).The reaction mixture was stirred overnight at room temperature andconcentrated on a rotary evaporator. The resulting residue waschromatographed (ethyl acetate:hexanes 1:1 then ethyl acetate andfinally methanol:methylene chloride 1:9 as the eluant) to provide thedesired product as a light yellow solid (340 mg, 49%). MS, m/z451.3=M+1.

[0862] The title compound was prepared by treating a solution of theresulting thiourea (340 mg, 0.75 mmol) and triethylamine (230 μL, 1.65mmol) in dry acetonitrile (4 mL) with mercury (II) chloride (225 mg,0.83 mmol) and morpholine (200 μL, 2.23 mmol). The reaction mixture wasstirred at room temperature for 4 h then filtered through a 0.45 μmfilter disc. The resulting filtrate was filtered through a column ofsilica (5% methanol/methylene chloride as the eluant) and the resultingcrude product was further purified by HPLC using a 20×250 mm C₁₈ reversephase column with the method being 20% acetonitrile in water toacetonitrile. MS, m/z 504.6=M+1.

[0863] The following examples were prepared by Method D in a parallelfashion:

Example 23

[0864]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-pyrrolidin-1-yl-methyl}-carbamicacid ethyl ester. MS, m/z 461=M+1.

Example 24

[0865]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-piperidin-1-yl-methyl}-carbamicacid ethyl ester. MS, m/z 477=M+1.

Example 25

[0866]{Azepan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 490=M+1.

Example 26

[0867]{Azocan-1-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 504=M+1.

Example 27

[0868]1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-ethoxycarbonylimino-methyl}-piperidine-4-carboxylicacid ethyl ester. MS, m/z 548=M+1.

Example 28

[0869]1-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-ethoxycarbonylimino-methyl}-piperidine-3-carboxylicacid ethyl ester. MS, m/z 548=M+1.

Example 29

[0870][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 545=M+1.

Example 30

[0871]{[1,4′]Bipiperidinyl-1′-yl-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 559=M+1.

Example 31

[0872][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(4-phenyl-piperazin-1-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 553=M+1.

Example 32

[0873][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(4-ethyl-piperazin-1-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 505=M+1.

Example 33

[0874]{(4-Acetyl-piperazin-1-yl)-[1-(4-cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-methylene}-carbamicacid ethyl ester. MS, m/z 519=M+1.

Example 34

[0875]4-{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-ethoxycarbonylimino-methyl}-piperazine-1-carboxylicacid ethyl ester. MS, m/z 549=M+1.

Example 35

[0876][[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylamino]-(3,3,5-trimethyl-6-aza-bicyclo[3.2.1]oct-6-yl)-methylene]-carbamicacid ethyl ester. MS, m/z 544=M+1.

Example 36

[0877]2-(7-Fluoro-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide.

[0878] To a stirred solution of aluminum chloride (7.13 g, 53.5 mmol) innitromethane (40 mL) at 0° C. was added ethyl isothiocyanato formate(3.5 g, 26.8 mmol). The reaction was stirred at 0° C. for 1 h and thenat room temperature for 48 h. The reaction mixture was then poured overcrushed ice and filtered to give 2.0 g of an orange solid. The solid wasdissolved in pyridine (20 mL) and heated at reflux for 4 h. The reactionwas diluted with methylene chloride and washed with water. The organicfraction was dried over anhydrous sodium sulfate and evaporated on arotary evaporator. The crude product was purified by flash columnchromatography over silica gel using 25% EtOAc and hexane to give 0.27 gof 7-fluoro-4-thioxo-3,4-dihydro-benzo[e][1,3]oxazin-2-one (5.1%).

[0879] To the above intermediate (0.135 g, 0.685 mmol) and2-amino-5,5-dimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide (0.251 g, 0.685 mmol) in dryTHF(10 mL) was added diisopropylethyl amine (0.36 mL, 2.06 mmol) and2-chloro-1-methylpyridinium iodide(0.288 g, 0.89 mmol). The reaction wasstirred at room temperature for 48 h. Solvent was evaporated and theresidue dissolved in methylene chloride, washed with water, dried overanhydrous sodium sulfate and evaporated. The crude product was purifiedinitially by flash column chromatography over silica gel using 10%MeOH/methylene chloride (0.25 g, 79.8%). Final purification by HPLCafforded the title compound, 1HNMR and MS were consistent with thedesired product; MS: 458 (M+1).

Example 37

[0880]N-(4-Cyano-1-propyl-piperidin-4-yl)-3-(4,4-dimethyl-cyclohexyl)-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-propionamide.

[0881] To a solution of 4,4-dimethyl cyclohexanone (4.60 g, 36.5 mmol)in dry THF (82 mL) cooled in a dry ice/acetone bath, was added sodiumbis (trimethylsilyl)amide (38 mL of a 1.0 M solution in THF, 38 mmol).The reaction mixture was stirred under an argon atmosphere at −78° C.for 30 min. A solution of 2-(N,N-bistrifluoromethanesulfonyl)amino-5-chloropyridine (15 g, 37.7 mmol) in dryTHF (20 mL) was introduced via syringe and the resulting solution waswarmed to room temperature and stirred overnight. The reaction mixturewas washed with half saturated brine (60 mL) and the aqueous phase wasextracted with diethyl ether. The combined organic extracts were dried(MgSO₄) and concentrated to provide a dark brown oil (23 g).Chromatography over silica gel using petroleum ether as the eluantprovided trifluoro-methane sulfonic acid 4,4-dimethyl-cyclohexyl-1-enylester as a colorless liquid (5.2 g, 56%). ¹H NMR (400 MHz, CDCl₃) δ 0.98(s, 6H), 1.53 (t, J=6.5 Hz, 2H), 1.95-1.99 (m, 2H), 2.30-2.40 (m, 2H),5.65-5.70 (m, 1H).

[0882] A mixture of the above triflate ester (2.26 g, 8.75 mmol), Cbzdehydroalanine methyl ester (2.10 g, 8.93 mmol), Pd (OAc)₂ (160 mg, 0.71mmol), and KOAc (3.42 g, 34.8 mmol) in dry DMF was stirred at roomtemperature for 24 h. The reaction mixture was diluted with water (400mL) and extracted with EtOAc (2×150 mL). The combined organic extractswere dried (MgSO₄) and concentrated. Chromatography of the resultingresidue over silica gel using 1:20 EtOAc/hexanes then 3:17 EtOAc/hexanesprovided2-benzyloxycarbonylamino-3-(4,4-dimethyl-cyclohex-1-enyl)-acrylic acidmethyl ester as a yellow oil (1.38 g, 46%). ¹H NMR (400 MHz, CDCl₃) δ0.88 (s, 6H), 1.34 (t, J=6.4 Hz, 2H), 1.95-2.00 (m, 2H), 2.23-2.30 (m,2H), 3.74 (s, 3H), 5.15 (s, 2H), 5.90-6.10 (m, 1H), 6.10-6.15 (m, 1H),7.0 (s, 1H), 7.25-7.36 (m, 5H). m/z 382.4 (MK⁺).

[0883] A suspension of the above acrylic acid ester (2.18 g, 6.35 mmol),Boc anhydride (1.52 g, 6.96 mmol), and 10% Pd/C (300 mg) in MeOH wasshaken on a Parr apparatus under 40 psi of hydrogen gas for 17 h. Thereaction mixture was filtered through a pad of diatomaceous earth andconcentrated to provide2-tert-butoxycarbonylamino-3-(4,4-dimethyl-cyclohexyl)-propionic acidmethyl ester as a yellow oil (1.87 g, 94%). ¹H NMR (400 MHz, CDCl₃) δ0.85 (s, 3H), 0.88 (s, 3H), 1.05-1.20 (m, 5H), 1.21-1.40 (m, 2H), 1.44(s, 9H), 1.45-1.59 (m, m, 2H), 1.60-1.78 (m, 2H), 3.72 (broad s, 3H),4.27-4.40 (m, 1H), 4.82-4.96 (m, 1H).

[0884] A suspension of the above methyl ester (1.87 g, 5.97 mmol) andlithium hydroxide monohydrate (1.76 g, 41.9 mmol) in THF (18 mL), MeOH(6 mL), and water (6 mL) was stirred at room temperature for 4 h. Thereaction mixture was acidified with 10% citric acid (aqueous) andextracted with diethyl ether (3×100 mL). The combined organic layerswere dried (MgSO₄) and concentrated to provide a the correspondingcarboxylic acid as a white foam (1.21 g, 68%). ¹H NMR (400 MHz, DMSO d₆)δ 0.83 (s, 3H), 0.85 (s, 3H), 0.87-1.10 (m, 4H), 1.10-1.46 (m, 3H), 1.35(s, 9H), 1.46-1.60 (m, 4H), 3.88-3.94 (m, 1H), 7.0 (d, 8.2 Hz, 1H),11.7-12.9 (broad s, 1H).

[0885] Isobutyl chloroformate (0.55 mL, 4.24 mmol) was added dropwise toa solution of the above carboxylic acid (1.21 g, 4.04 mmol) and N-methylmorpholine (0.89 mL, 8.10 mmol) in dry THF cooled to 0° C. The reactionmixture was stirred at 0° C. for 1 h. A solution of4-amino-1-propyl-piperidine-4-carbonitrile (780 mg, 4.65 mmol) in dryTHF (5 mL) was added and the reaction mixture was allowed to warm toroom temperature and stirred overnight. Volatiles were removed on arotary evaporator and the resulting residue was dissolved in EtOAc (50mL) and washed with saturated Na₂CO₃ (50 mL). The organic phase wasdried (MgSO₄) and concentrated. Chromatography of this crude materialover silica gel using a gradient of dichloromethane to 5% MeOH indichloromethane provided[1-(4-cyano-1-propyl-piperidin-4-ylcarbamoyl)-2-(4,4-dimethyl-cyclohexyl)-ethyl]-carbamicacid tert-butyl ester as a white foam (1.17 g, 65%). ¹H NMR (400 MHz,CDCl₃) δ 0.85 (s, 3H), 0.88 (s, 3H), 0.89 (t, J=7.3 Hz, 3H), 1.05-1.30(m, 6H), 1.30-1.40 (m, 2H), 1.45 (s, 9H), 1.40-1.60 (m, 5H), 1.70-1.83(m, 1H), 1.87-2.02 (m, 2H), 2.32-2.54 (m, 6H), 2.68-2.90 (m, 2H),4.00-4.10 (m, 1H), 4.80-5.00 (m, 1H), 6.70-6.90 (m, 1H); m/z 449.5(M+H)⁺, 447.4 (M−H)⁻.

[0886] The above tert-butyl ester (1.17 g, 2.6 mmol) was dissolved in asolution of HCl in 1,4-dioxane (10.0 mL of a 4.0 M solution, 40 mmol)and stirred under an active sweep of argon gas for 10 min. The solutionwas concentrated on a rotary evaporator then taken up in CHCl₃ (50 mL)and concentrated again to provide the amine dihydrochloride as a whitepowder (1.05 g, 95%). m/z=349.5 (M+H)⁺.

[0887] A suspension of 4-chloro benzoxazin-2-one (500 mg, 2.69 mmol),the above amine salt (400 mg, 0.95 mmol), and polystyrene supporteddiisopropylamine (2.40 g, 8.40 mmol) in dry acetonitrile was heated at50° C. for 5 h. The reaction mixture was filtered through a pad ofdiatomaceous earth and the filtrate was concentrated. The resultingresidue was chromatographed over silica gel using methylene chloridethen 2.5% MeOH in methylene chloride and finally 10% MeOH in methylenechloride as the eluant to provide the title compound as a white solid(45 mg, 10%). ¹H NMR (400 MHz, DMSO d₆) δ 0.82 (t, J=7.5 Hz, 3H), 0.83(s, 3H), 0.84 (s, 3H), 1.00-1.20 (m, 5H), 1.25-1.42 (m, 5H), 1.48-1.58(m, 2H), 1.60-1.70 (m, 1H), 1.80-1.92 (m, 2H), 2.10-2.30 (m, 6H),2.55-2.68 (m, 2H), 4.83-4.92 (m, 1H), 7.29 (d, J=8.3 Hz, 1H), 7.36 (t,J=7.7 Hz, 1H), 7.73 (t, J7.3 Hz, 1H), 8.36 (d, J=8.1 Hz, 1H), 8.73 (s,1H), 8.98-9.10 (m, 1H); m/z=494.5 (M+H)⁺, 492.4 (M−H)⁻.

Example 38

[0888]4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide.

[0889] A mixture of 4-chloro-1,2-dihydro-2-oxo-quinazoline (1.0 g, 5.5mmol), iodomethane (0.86 mL, 2.5 equiv.) and potassium carbonate (1.91g, 2.5 equiv.) in DMF (15 mL) was heated at 80° C. for 90 min before thesolvent was removed at reduced pressure at 80° C. The residue was takenup in dichloromethane and filtered. The filtrate was concentrated andcolumn chromatography on silica gel (eluent: EtOAc) gave the N-methylanalog (0.21 g, 19.5%).

[0890] A mixture of the above intermediate (100 mg, 0.5 mmol),2-amino-4,4-dimethylpentanoic acid(4-cyano-1-propyl-piperidin-4-yl)amide (151 mg, 0.5 mmol), Cu (powder,66 mg, 1 mmol) and potassium carbonate (285 mg, 2 mmol) in NMP (3 mL)was heated at 150° C. for 16 h. After it was cooled to room temperature,it was filtered. The filtrate was diluted with water and extracted withdichloromethane. The organic phase was washed with brine, dried (sodiumsulfate), concentrated and chromatographed on silica gel affording thetitle compound (101 mg, 44.6%); MS: 453 (M+1).

Example 39

[0891]{[1-(4-Cyano-1-methyl-piperidin-4-ylcarbamoyl)-2-cyclohexyl-ethylimino]-morpholin-4-yl-methyl}-carbamicacid 2,2-dimethyl-propyl ester.

[0892] To a solution of sodium thiocyanate (4.46 g, 55 mmol) in 50 mL ofacetonitrile was added neopentyl chloroformate (6.15 mL, 50 mmol). Thismixture was heated at 80° C. for 2 h. After cooling to room temperature,the solid was removed by filtration and the filtrate was used as a 1 Mstock solution of neopentyl isothiocyanatoformate.

[0893]2-Amino-N-(4-cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-propionamidedihydrochloride salt (6.33 g, 17.32 mmol) was suspended in 50 mL ofmethylene chloride. Triethylamine (5.00 mL, 35.9 mL) was added. To thissolution at 0° C. was added the above solution (20 mL, 20 mmol). Thismixture was stirred at 0° C. for 1 h. The solvent was removed in vacuo.The residue was purified by flash chromatography on silica gel elutingwith 5% MeOH in ethyl ether (Rf=0.2) to give the thiourea (4.76 g, 59%)as a yellow oil; MS: M+1=466.

[0894] The thiourea (4.67 g, 10.0 mmol) was dissolved in 30 mL of THF.Copper sulfate on silica gel (4.00 g, 10.0 mmol) was added followed by 1mL of triethylamine. This mixture was stirred at room temperature for 30min. Morpholine (1.25 mL, 20 mmol) was added. The reaction mixture washeated under reflux for 2 h. Another 4 g of copper sulfate on silica geland 1.25 mL of morpholine were added. The reaction mixture was heatedfor an additional 2 h. After cooling to room temperature, solids wereremoved by filtration and washed with acetonitrile. The filtrate wasconcentrated under reduced pressure and then purified by flashchromatography on silica gel, eluting with a mixture of ethyl ether,methylene chloride and MeOH (2:1:0.1) to give a yellow oil. This oil wascrystalized from ethyl ether and hexane to give the title compound (1.81g, 35%) as a white solid; M+1=519.

Example 40

[0895] 2-Amino-4,4,5-trimethyl-hexanoic acid(4-cyano-1-propyl-piperidin-4-yl)-amide bis-hydrochloride.

[0896] Lithium diisopropylamide (1.5 M solution incyclohexane/THF/ethylbenzene) (113 mL, 169 mmol, 1.1 equiv) was syringedinto a 1000 mL round-bottom flask under a blanket of Ar. Dry THF (150mL) was added and the mixture was cooled to −78° C. with adry-ice/acetone bath. 3-Methyl-butanoic acid ethyl ester (20 g, 23 mL,154 mmol, 1.0 equiv) was added dropwise from a syringe over a 10 minperiod followed by stirring at −78° C. for 1 h. Methyl iodide (10.5 mL,169 mmol, 1.1 equiv) was added dropwise from a syringe over a 10 minperiod and the creamy mixture was stirred for 1 h at −78° C., resultingin a very thick mixture. The dry-ice bath was removed and replaced withan ice bath at 0° C. Another 150 mL of dry THF was added followed byanother addition of LDA (113 mL, 169 mmol, 1.1 equiv). The resultingmixture was stirred for 10 min and then the flask was re-immersed in adry-ice/acetone bath. Stirring was continued for another 50 min and thenmethyl iodide was added dropwise (10.5 mL, 169 mmol, 1.1 equiv) and thedry-ice/acetone bath was removed and the resulting mixture was stirredat ambient temperature for 14 h. The reaction mixture was quenched with3 mL of conc. HCl and 2 N HCl was added until the pH was adjusted to <1.The mixture was further diluted with 150 mL water and 500 mL Et₂O. Thelayers were separated and the organic layer was washed with 1×100 mL 2 NHCl, 1×100 mL saturated NaHCO₃, and 1×200 mL brine. The organic layerwas dried over Na₂SO₄ and then concentrated in vacuo to provide2,2,3-trimethylbutanoic acid ethyl ester as an orange oil mixed withethyl benzene (36.4 g of which 22.1 g was product by NMR). The mixturewas used without further purification.

[0897] A 500 mL round-bottom-flask equipped with a stir bar was flushedwith Ar and charged with 50 mL dry THF and a 1 M solution of LAH in Et₂O(87.5 mL, 87.5 mmol, 0.625 equiv). The solution was cooled to 0° C. withan ice bath and the above ethyl ester (22.1 g, 140 mmol, 1.0 equiv)(approximately a 50% solution in ethylbenzene) was added dropwise atsuch a rate that the solution did not reflux (required 50 min). Afteraddition of the ester, the reaction was stirred at 0° C. for 2 h andthen at ambient temperature for 14 h. The reaction solution wasre-cooled to 0° C. and carefully quenched by addition of EtOAc. 1 N NaOHwas added until a granular precipitate formed (7.5 mL). The mixture wasfiltered on a pad of diatomaceous earth which was then washed 3×100 mLEt₂O. The organics were combined and dried over Na₂SO₄. The solution wasdecanted and concentrated in vacuo to yield 2,2,3-trimethyl-butanol2,2,3-trimethyl-butanol as a nearly colorless oil (11.7 g of alcohol in15.4 g of a mix with ethylbenzene). The crude product was used withoutfurther purification.

[0898] A 1000 mL round-bottom-flask was equipped with a stir bar,flushed with Ar and charged with 300 mL dry CH₂Cl₂ and oxalyl chloride(13.2 mL, 151 mmol, 1.5 equiv). The solution was cooled to −78° C. witha dry-ice/acetone bath. Dry DMSO (21.5 mL, 302 mmol, 3.0 equiv) wasadded dropwise over a 30 min period (vigorous gas evolution). The abovealcohol (11.7 g, 100 mmol, 1.0 equiv) was added (with residualethylbenzene) over a 10 min period. The resulting solution was stirredfor 90 min. Triethylamine (56 mL, 403 mmol, 4.0 equiv) was added over 5min and the cold-bath was removed. The resulting creamy white mixturewas stirred at room temperature over 1.5 h. The reaction mixture wascarefully diluted with 200 mL water (more gas evolution). Layers wereseparated and the organic phase was washed with 1×100 mL 2 N HCl and1×100 mL brine. The organic layer was dried over Na₂SO₄, decanted andconcentrated in vacuo. The crude aldehyde was distilled fractionallythrough a 4 inch Vigoreux column at 57-67° C. at 15 mm Hg to provide the2,2,3-trimethyl-butanal (9.1 g) as a colorless oil.

[0899] A clean and dry 250 mL round-bottom flask was equipped with astir bar and flushed with Ar. Dry THF was added (40 mL) followed byaddition of a 1.0 M solution of KO-t-Bu (32.2 mL, 32.2 mmol, 1.05equiv). The solution was cooled to −78° C. in a dry-ice/acetone bath.Ethyl isocyanoacetate (3.35 mL, 30.7 mmol, 1.0 equiv) was added dropwiseover a 10 min period. The resulting mixture was stirred an additional 5min followed by addition, via syringe, of 2,2,3-trimethyl-butanal (3.5g, 30.7 mmol, 1.0 equiv). The cold-bath was removed and resultingmixture was stirred at room temperature for 1 h. The reaction mixturewas diluted by addition of a mix of 125 mL Et₂O, 20 g ice, 2 mL AcOH.After the ice melted, 50 mL of water was added and the layers were mixedand separated. The organic layer was washed with 1×50 mL sat. NaHCO₃ anddried over Na₂SO₄. The organic layer was decanted and concentrated. Thecrude enamide was purified by flash chromatography on silica gel usingCH₂Cl₂ to 4% MeOH in CH₂Cl₂ to provide2-formylamino-4,4,5-trimethyl-hex-2-enoic acid ethyl ester as a thickoil (4.54 g); MS: 228 (M+1).

[0900] The above ethyl ester (4.54 g, 20 mmol, 1.0 equiv) was dissolvedin 35 mL of MeOH in a Parr bottle followed by addition of PtO₂ (1 g, 4.4mmol, 0.22 equiv). The mixture was shaken on a Parr hydrogenationapparatus for 4 days at which time MS showed consumption of the startingmaterial; MS: 230 (M+1), 216 (M+1 of methyl ester). The liquid wascarefully decanted and the Pt was washed 3×20 mL MeOH followed each timeby decantation, being careful not to allow the Pt to dry (if allowed todry, the Pt may ignite). The MeOH solutions were combined andconcentrated to a thick oil that was suspended in 25 mL of 6 N HCl andthe mixture was refluxed for 4 h during which time 5 mL of conc. HCl wasadded at the end of each of the first 3 h. The mixture was cooled andthe water and excess HCl were removed on a rotovap at a bath temperatureof 70° C. After about 50% concentration, a flaky crystalline solidformed. The mixture was cooled to 0° C. and the precipitate wascollected by filtration. The filtrate was again concentrated by about50% and cooled again to 0° C. to provide a second crop of crystals. Thecrystals were combined and dried under high vacuum to provide2-amino-4,4,5-trimethyl-hexanoic acid hydrochloride as an off-whitecrystalline solid (2.32 g); MS: 174 (M-Cl+1).

[0901] The above amino acid salt (2.32 g, 11.1 mmol, 1.0 equiv) wasdissolved in 100 mL of 50/50 dioxane/4 N NaOH. The solution was cooledto 0° C. and Boc anhydride (3.6 g, 16.6 mmol, 1.5 equiv) was added. Thecold-bath was removed and the reaction stirred at ambient temperaturefor 16 h. The pH was carefully adjusted to 2 with conc. HCl, and theproduct was extracted with 3×100 mL CH₂Cl₂. The organic layers werecombined and dried over Na₂SO₄. The solution was decanted andconcentrated using 100 mL of hexane as a chaser to provide a thickglass, which was triturated with 100 mL of hexane. After vigorousstirring for 4 h, a waxy solid resulted which was filtered and dried inair to provide 2-tert-butoxycarbonylamino-4,4,5-trimethyl-hexanoic acid(1.42 g).

[0902] The above carboxylic acid (0.400 g, 1.46 mmol, 1.0 equiv) wasdissolved in 15 mL of THF and cooled to 0° C. N-Methylmorpholine (0.338mL, 3.07 mmol, 2.1 equiv) was added followed by dropwise addition, over1 min, of isobutylchloroformate (0.19 mL, 1.0 equiv). A whiteprecipitate immediately formed. The mixture was stirred for 30 min atwhich time a solution of 4-amino-4-cyano-1-propyl-piperidine (0.257 g,1.54 mmol, 1.05 equiv) in 5 mL of THF was added. The resulting mixturewas stirred for 16 h at room temperature. The volatiles were removed ona rotovap and the resulting paste was triturated with 100 mL water withvigorous stirring to give a fluffy white solid which was collected byfiltration. The solid was washed with 100 mL of water and dried undervacuum to yield the desired product as an off-white powder (0.521 g);MS: 423 (M+1). The Boc protecting group was removed by treatment of thesolid under Ar with 20 mL of 4N HCl in dioxane for 1 h. The resultingpaste was diluted with 40 mL of Et₂O and the solid was filtered underAr. The resulting paste was washed 1×25 mL Et₂O and dried in vacuo toyield the title compound as the dihydrochloride salt; MS: 323 (M+1).

Example 41

[0903] 2-tert-Butoxycarbonylamino-5,5-dimethyl-hexanoic acid

[0904] N-(Benzyloxycarbonyl)-α-phosphonoglycine trimethyl ester (2 g,6.0 mmol, 1.0 equiv) was dissolved in dry THF (20 mL).tert-Butylacetaldehyde (0.758 mL, 6.0 mmol, 1.0 equiv) and DBU (0.903mL, 6.0 mmol, 1.0 equiv) were added and the reaction mixture was stirredfor 16 h. The solution was diluted with 100 mL of CH₂Cl₂ and washed with1×50 mL water, and 1×50 mL brine. The organic layer was dried overNa₂SO₄, decanted and concentrated in vacuo to provide2-benzyloxycarbonylamino-5,5-dimethyl-hex-2-enoic acid methyl ester as athick oil (1.73 g, 94%) which was used without further purification; MS:306 (M+1).

[0905] The above ester (1.73 g, 5.67 mmol, 1.0 equiv) was dissolved in aParr bottle with Boc anhydride (1.36 g, 6.23 mmol, 1.0 equiv) and MeOH(35 mL). Pd on carbon (Degussa type) (0.5 g) was added. The mixture wasshaken under 50 psi H₂ for 16 h. The mixture was filtered ondiatomaceous earth followed by washing of the diatomaceous earth with3×50 mL MeOH. The organics were combined and concentrated to provide2-tert-butoxycarbonylamino-5,5-dimethyl-hexanoic acid methyl ester as avery thick oil which was used without further purification.

[0906] The above ester (1.31 g, 4.79 mmol, 1.0 equiv) was dissolved in50 mL of MeOH. 1 N LiOH (50 mL) was added and the mixture was stirred 16h. Concentrated HCl was added carefully until the pH approached 2 atwhich time a bright white solid precipitated. The solid was collected byfiltration and washed 2×20 mL water and dried under vacuum to providethe title compound (1.05 g, 85%); MS: 258 (M−1).

METHODS OF THERAPEUTIC USE

[0907] The compounds of the invention are useful in inhibiting theactivity of cathepsin S, K, F, L and B. In doing so, these compounds areuseful in blocking disease processes mediated by these cysteineproteases.

[0908] Compounds of this invention effectively block degradation of theinvariant chain to CLIP by cathepsin S, and thus inhibit antigenpresentation and antigen-specific immune responses. Control of antigenspecific immune responses is an attractive means for treating autoimmunediseases and other undesirable T-cell mediated immune responses. Thus,there is provided methods of treatment using the compounds of thisinvention for such conditions. These encompass autoimmune diseases andother diseases involving inappropriate antigen specific immune responsesincluding, but not limited to, rheumatoid arthritis, systemic lupuserythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis,Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis,scleroderma, glomerulonephritis, dermatitis including contact and atopicdermatitis, insulin-dependent diabetes mellitus, endometriosis andasthma including allergic asthma. The compounds of the invention canalso be used to treat other disorders associated with extracellularproteolysis such as Alzheimer's disease and atherosclerosis. Thecompounds of the invention can also be used to treat other disordersassociated with inappropriate autoimmune responses, T-cell mediatedimmune responses, or extracellular proteolysis mediated by cathepsin S,unrelated to those listed above or discussed in the Background of theInvention. Therefore, the invention also provides methods of modulatingan autoimmune disease comprising administering to a patient in need ofsuch treatment a pharmaceutically effect amount of a compound accordingto the invention.

[0909] Compounds of the invention also inhibit cathepsin K. In doing so,they may block inappropriate degradation of bone collagen and other bonematrix proteases. Thus, there is provided a method for treating diseaseswhere these processes play a role such as osteoporosis. Inhibition ofcathepsins F, L, and B are also within the scope of the invention due tosimilarity of the active sites in cysteine proteases as described above.

[0910] For therapeutic use, the compounds of the invention may beadministered in any conventional dosage form in any conventional manner.Routes of administration include, but are not limited to, intravenously,intramuscularly, subcutaneously, intrasynovially, by infusion,sublingually, transdermally, orally, topically or by inhalation. Thepreferred modes of administration are oral and intravenous.

[0911] The compounds of this invention may be administered alone or incombination with adjuvants that enhance stability of the inhibitors,facilitate administration of pharmaceutical compositions containing themin certain embodiments, provide increased dissolution or dispersion,increase inhibitory activity, provide adjunct therapy, and the like,including other active ingredients. Advantageously, such combinationtherapies utilize lower dosages of the conventional therapeutics, thusavoiding possible toxicity and adverse side effects incurred when thoseagents are used as monotherapies. Compounds of the invention may bephysically combined with the conventional therapeutics or otheradjuvants into a single pharmaceutical composition. Advantageously, thecompounds may then be administered together in a single dosage form. Insome embodiments, the pharmaceutical compositions comprising suchcombinations of compounds contain at least about 15%, but morepreferably at least about 20%, of a compound of the invention (w/w) or acombination thereof. Alternatively, the compounds may be administeredseparately (either serially or in parallel). Separate dosing allows forgreater flexibility in the dosing regime.

[0912] As mentioned above, dosage forms of the compounds of thisinvention include pharmaceutically acceptable carriers and adjuvantsknown to those of ordinary skill in the art. These carriers andadjuvants include, for example, ion exchangers, alumina, aluminumstearate, lecithin, serum proteins, buffer substances, water, salts orelectrolytes and cellulose-based substances. Preferred dosage formsinclude, tablet, capsule, caplet, liquid, solution, suspension,emulsion, lozenges, syrup, reconstitutable powder, granule, suppositoryand transdermal patch. Methods for preparing such dosage forms are known(see, for example, H. C. Ansel and N. G. Popovish, Pharmaceutical DosageForms and Drug Delivery Systems, 5th ed., Lea and Febiger (1990)).Dosage levels and requirements are well-recognized in the art and may beselected by those of ordinary skill in the art from available methodsand techniques suitable for a particular patient. In some embodiments,dosage levels range from about 10-1000 mg/dose for a 70 kg patient.Although one dose per day may be sufficient, up to 5 doses per day maybe given. For oral doses, up to 2000 mg/day may be required. As theskilled artisan will appreciate, lower or higher doses may be requireddepending on particular factors. For instance, specific dosage andtreatment regimens will depend on factors such as the patient's generalhealth profile, the severity and course of the patient's disorder ordisposition thereto, and the judgment of the treating physician.

ASSESSMENT OF BIOLOGICAL PROPERTIES

[0913] Expression and Purification of recombinant human Cathepsin S

[0914] Cloning of Human Cathepsin S:

[0915] U937 RNA was subjected to reverse transcriptase/polymerase chainreaction with primer A (5′cacaatgaaacggctggtttg 3′) and primer B(5′ctagatttctgggtaagaggg 3′) designed to specifically amplify thecathepsin S cDNA. The resulting 900 bp DNA fragment was subcloned intopGEM-T (Promega) and sequenced to confirm its identity. This constructwas used for all subsequent manipulations. This procedure is typical forcloning of known genes and is established in its field.

[0916] Human Pre-Pro-Cat S was removed from pGem-T vector (Promega, 2800Woods Hollow Rd, Madison, Wis. 53711) by digestion with restrictionenzyme SacII, followed by treatment with T4 DNA polymerase to generate ablunt end, and a second restriction enzyme digest with SalI. It wassubcloned into pFastBac1 donor plasmid (GibcoBRL, 8717 Grovemont Cr.,Gaithersburg, Md. 20884) which had been cut with restriction enzymeBamH1 and blunt-ended and then cut with restriction enzyme SalI. Theligation mixture was used to transform DH5a competent cells (GibcoBRL)and plated on LB plates containing 100 ug/ml ampicillin. Colonies weregrown in overnight cultures of LB media containing 50 ug/ml Ampicillin,plasmid DNA isolated and correct insert confirmed by restriction enzymedigestion. Recombinant pFastBac donor plasmid was transformed intoDH10Bac competent cells (GibcoBRL). Large white colonies were pickedfrom LB plates containing 50 ug/ml kanamycin, 7 ug/ml gentamicin, 10ug/ml tetracycline, 100 ug/ml Bluo-gal, and 40 ug/ml IPTG. DNA wasisolated and used to transfect Sf9 insect cells using CellFECTIN reagent(GibcoBRL). Cells and supernatant were harvested after 72 hours. Viralsupernatant was passaged twice and presence of Cat S confirmed by PCR ofthe supernatant. SF9 cells were infected with recombinant baculovirus ata MOI of 5 for 48-72 hrs. Cell pellet was lysed and incubated in bufferat pH 4.5 at 37 for 2 hours to activate Cat S from pro-form to activemature form (Bromme, D & McGrath, M., Protein Science, 1996, 5:789-791.)Presence of Cat S was confirmed by SDS-PAGE and Western blot usingrabbit anti-human proCat S.

[0917] Inhibition of Cathepsin S

[0918] Human recombinant cathepsin S expressed in Baculovirus is used ata final concentration of 10 nM in buffer. Buffer is 50 mM Na acetate, pH6.5, 2.5 mM EDTA, 2.5 mM TCEP. Enzyme is incubated with either compoundor DMSO for 10 min at 37° C. Substrate 7-amino-4-methylcoumarin,CBZ-L-valyl-L-valyl-L-arginineamide (custom synthesis by MolecularProbes) is diluted to 20 uM in water (final concentration of 5 M), addedto assay and incubated for additional 10 minutes at 37° C. Compoundactivity is measured by diminished fluorescence compared to DMSO controlwhen read at 360 nm excitation and 460 nm emission.

[0919] Examples listed above were evaluated for inhibition of cathepsinS in the above assay. All had IC₅₀ values of 100 micromolar or below.

[0920] Inhibition of Cathepsin K, F, L and B:

[0921] Inhibition of these enzymes by particular compounds of theinvention may be determined without undue experimentation by using artrecognized methods as provided hereinbelow each of which is incorporatedherein by reference:

[0922] Cathepsin B, and L assays are to be found in the followingreferences:

[0923] 1. Methods in Enzymology, Vol.244, Proteolytic Enzymes: Serineand Cysteine Peptidases, Alan J. Barrett, ed. Cathepsin K assay is to befound in the following reference:

[0924] 2. Bromme, D., Okamoto, K., Wang, B. B., and Biroc, S. (1996) J.Biol. Chem. 271, 2126-2132.

[0925] Cathepsin F assays are to be found in the following references:

[0926] 3. Wang, B., Shi, G. P., Yao, P. M., Li, Z., Chapman, H. A., andBromme, D. (1998) J. Biol. Chem. 273, 32000-32008.

[0927] 4. Santamaria, I., Velasco, G., Pendas, A. M., Paz, A., andLopez-Otin, C (1999) J. Biol. Chem. 274, 13800-13809.

[0928] Preferred compounds to be evaluated for inhibition of CathepsinK, F, L and B in the above assays desirably have IC₅₀ values of 100micromolar or below.

What is claimed is:
 1. A compound of the formula (Ia):

wherein for the Formula (Ia), the components

is chosen from A1-A25 in the table below;

is chosen from B1-B49 in the table below and

is chosen from C1-C48 in the table below; A

B

C

A1

B1

C1

A2

B2

C2

A3

B3

C3

A4

B4

C4

A5

B5

C5

A6

B6

C6

A7

B7

C7

A8

B8

C8

A9

B9

C9

A10

B10

C10

A11

B11

C11

A12

B12

C12

A13

B13

C13

A14

B14

C14

A15

B15

C15

A16

B16

C16

A17

B17

C17

A18

B18

C18

A19

B19

C19

A20

B20

C20

A21

B21

C21

A22

B22

C22

A23

B23

C23

A24

B24

C24

A25

B25

C25

B26

C26

B27

C27

B28

C28

B29

C29

B30

C30

B31

C31

B32

C32

B33

C33

B34

C34

B35

C35

B36

C36

B37

C37

B38

C38

B39

C39

B40

C40

B41

C41

B42

C42

B43

C43

B44

C44

B45

C45

B46

C46

B47

C47

B48

C48

B49

or the pharmaceutically acceptable salts, esters, tautomers, individualisomers and mixtures of isomers thereof.
 2. A compound chosen from:N-(2-Cyano-octahydro-quinolizin-2-yl)-3-cyclohexyl-2-(1,1-dioxo-1H-1λ-benzo-3-ylamino)-propionamide;N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(5,6-difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;2-(5,6-Difluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide;2-(6-Fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-4,4-dimethyl-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide;N-(4-Cyano-1-methyl-piperidin-4-yl)-3-cyclohexyl-2-(6-fluoro-3-oxo-2,3-dihydro-isoindol-1-ylideneamino)-propionamide;4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide;4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide;3-tert-Butylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;3-Benzylsulfanyl-N-(4-cyano-1-propyl-piperidin-4-yl)-2-(2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-propionamide;4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide;3-Cyano-3-[4,4-dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoylamino]-azepane-1-carboxylicacid benzyl ester;4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(3-cyano-1-propyl-azepan-3-yl)-amide;4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid(4-cyano-1-propyl-azepan-4-yl)-amide;N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(6-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;N-(4-Cyano-1-methyl-piperidin-4-yl)-4-cyclohexyl-2-(7-methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-ylideneamino)-butyramide;2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide; or the pharmaceuticallyacceptable salts, esters, tautomers, individual isomers and mixtures ofisomers thereof.
 3. A compound chosen from:2-(7-Methoxy-2-oxo-2,3-dihydro-benzo[e][1,3]oxazin-4-yldeneamino)-5,5-dimethyl-hexanoicacid(4-cyano-1-propyl-piperidin-4-yl)-amide;4,4-Dimethyl-2-(2-oxo-2,3-dihydro-1H-quinazolin-4-ylideneamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide;4,4-Dimethyl-2-(1-methyl-2-oxo-1,2-dihydro-quinazolin-4-ylamino)-pentanoicacid (4-cyano-1-propyl-piperidin-4-yl)-amide;4,4-Dimethyl-2-(2-oxo-2H-benzo[e][1,3]oxazin-4-ylamino)-pentanoic acid[4-cyano-1-(5-methyl-thiophen-2-ylmethyl)-piperidin-4-yl]-amide; or thepharmaceutically acceptable salts, esters, tautomers, individual isomersand mixtures of isomers thereof.
 4. A pharmaceutical compositioncomprising a pharmaceutically effective amount of a compound accordingto claim
 1. 5. A pharmaceutical composition comprising apharmaceutically effective amount of a compound according to claim
 2. 6.A method of treating an autoimmune disease, said method comprisingadministering to a patient in need of such treatment a pharmaceuticallyeffective amount of a compound according to claim
 1. 7. A method oftreating an autoimmune disease, said method comprising administering toa patient in need of such treatment a pharmaceutically effective amountof a compound according to claim
 2. 8. The method according to claim 6wherein the autoimmune disease is rheumatoid arthritis, systemic lupuserythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis,Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis,scleroderma, glomerulonephritis, dermatitis, endometriosis orinsulin-dependent diabetes mellitus.
 9. The method according to claim 7wherein the autoimmune disease is rheumatoid arthritis, systemic lupuserythematosus, Crohn's disease, ulcerative colitis, multiple sclerosis,Guillain-Barre syndrome, psoriasis, Grave's disease, myasthenia gravis,scleroderma, glomerulonephritis, dermatitis, endometriosis orinsulin-dependent diabetes mellitus.
 10. A method of treatingAlzheimer's disease comprising administering to a patient in need ofsuch treatment a pharmaceutically effective amount of a compoundaccording to claim
 1. 11. A method of treating Alzheimer's diseasecomprising administering to a patient in need of such treatment apharmaceutically effective amount of a compound according to claim 2.12. A method of treating atherosclerosis comprising administering to apatient in need of such treatment a pharmaceutically effective amount ofa compound according to claim
 1. 13. A method of treatingatherosclerosis comprising administering to a patient in need of suchtreatment a pharmaceutically effective amount of a compound according toclaim
 2. 14. A method of treating osteoporosis comprising administeringto a patient in need of such treatment a pharmaceutically effectiveamount of a compound according to claim
 1. 15. A method of treatingosteoporosis comprising administering to a patient in need of suchtreatment a pharmaceutically effective amount of a compound according toclaim
 2. 16. A method of treating asthma comprising administering to apatient in need of such treatment a pharmaceutically effective amount ofa compound according to claim
 1. 17. A method of treating asthmacomprising administering to a patient in need of such treatment apharmaceutically effective amount of a compound according to claim 2.